Faculty Bibliography

BACKGROUND:Hyperthermia (heating to 43 °C) activates the innate immune system and improves bladder cancer chemosensitivity. OBJECTIVE:To evaluate the tissue penetration and safety of convective hyperthermia combined with intravesical mitomycin C (MMC) pharmacokinetics in live porcine bladder models using the Combat bladder recirculation system (BRS). METHODS:Forty 60 kg-female swine were anesthetized and catheterized with a 3-way, 16 F catheter. The Combat device was used to heat the bladders to a target temperature of 43 °C with recirculating intravesical MMC at doses of 40, 80, and 120 mg. Dwell-heat time varied from 30-180 min. Rapid necropsy with immediate flash freezing of tissues, blood and urine occurred. MMC concentrations were measured by liquid chromatography tandem-mass spectrometry. RESULTS:The Combat BRS system was able to achieve target range temperature (42-44 °C) in 12 mins, and this temperature was maintained as long as the device was running. Two factors increased tissue penetration of MMC in the bladder: drug concentration, and the presence of heat. In the hyperthermia arm, MMC penetration saturated at 80 mg, suggesting that with heating, drug absorption may saturate and not require higher doses to achieve the maximal biological effect. Convective hyperthermia did not increase the MMC concentration in the liver, heart, kidney, spleen, lung, and lymph node tissue even at the 120 mg dose. CONCLUSIONS:Convective bladder hyperthermia using the Combat BRS device is safe and the temperature can be maintained at 43 °C. Hyperthermia therapy may increase MMC penetration into the bladder wall but does not result in an increase of MMC levels in other organs.

BACKGROUND: The EMulate Therapeutics Halo system is an investigational non-sterile, non-invasive, non-thermal, non-ionizing, portable, home-use medical device that uses a specific, localized ultra-low radio frequency energy (ulRFER) cognate for the treatment of pediatric brain tumors.
METHOD(S): Sixteen patients with brain tumors consisting of diffuse midline glioma/diffuse intrinsic pontine glioma (DMG/DIPG, n=14), recurrent medulloblastoma (n=1), or anaplastic astrocytoma (n=1) - were treated with the Halo under FDA's single-patient compassionate use pathway, as protocol deviations in a glioblastoma trial, or under TGA's Special Access Scheme. Baseline information and on-treatment safety and exposure data were collected.
RESULT(S): Patients ranged in age from 4 to 28 years (median = 8 years) and were diagnosed 91 - 1399 days (median = 397 days) prior to treatment with the Halo system. Patients were treated for 2 - 52 weeks (median = 15 weeks), with 4 patients still alive (all with a diagnosis of DMG/DIPG), and 3 still on treatment (ranging 18 - 52 weeks). Two out of the 16 patients reported mild-moderate adverse events - one patient reported nausea, fatigue, and excessive sleepiness, and one patient reported vomiting. No device-related serious adverse events were reported. Other adverse events reported were generally associated with progressive disease. Unsolicited, anecdotal reports from some parents/caregivers noted improvements in mobility, speech, and visual acuity while on treatment.
CONCLUSION(S): The Halo system appears to be safe and feasible for the treatment of pediatric brain tumors. Given that therapy is delivered non-invasively and no device-related serious adverse events were reported, further prospective study of the investigational device is warranted

BACKGROUND AND PURPOSE/OBJECTIVE:Cardiac biomarkers may help identify stroke mechanisms and may aid in improving stroke prevention strategies. There is limited data on the association between these biomarkers and acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). We hypothesized that cardiac biomarkers (cardiac troponin and left atrial diameter [LAD]) would be associated with the presence of LVO. METHODS:Data were abstracted from a single center prospective AIS database over 18 months and included all patients with AIS with CT angiography of the head and neck. The presence of LVO was defined as proximal LVO of the internal carotid artery terminus, middle cerebral artery (M1 or proximal M2), or basilar artery. Univariate analyses and predefined multivariable models were performed to determine the association between cardiac biomarkers (positive troponin [troponin ≥0.1 ng/mL] and LAD on transthoracic echocardiogram) and LVO adjusting for demographic factors (age and sex), risk factors (hypertension, diabetes, hyperlipidemia, history of stroke, congestive heart failure, coronary heart disease, and smoking), and atrial fibrillation (AF). RESULTS:We identified 1234 patients admitted with AIS; 886 patients (71.8%) had vascular imaging to detect LVO. Of those with imaging available, 374 patients (42.2%) had LVO and 207 patients (23.4%) underwent thrombectomy. There was an association between positive troponin and LVO after adjusting for age, sex and other risk factors (adjusted OR 1.69 [1.08-2.63], P = .022) and this association persisted after including AF in the model (adjusted OR 1.60 [1.02-2.53], P = 0.043). There was an association between LAD and LVO after adjusting for age, sex, and risk factors (adjusted OR per mm 1.03 [1.01-1.05], P = 0.013) but this association was not present when AF was added to the model (adjusted OR 1.01 [0.99-1.04], P = .346). Sensitivity analyses using thrombectomy as an outcome yielded similar findings. CONCLUSIONS:Cardiac biomarkers, particularly serum troponin levels, are associated with acute LVO in patients with ischemic stroke. Prospective studies are ongoing to confirm this association and to test whether anticoagulation reduces the risk of recurrent embolism in this patient population.

BACKGROUND AND PURPOSE/OBJECTIVE:Patients with ischemic stroke of cardioembolic origin are at risk of visceral (renal or splenic) infarction. We hypothesized that serum troponin level at time of ischemic stroke would be associated with presence of visceral infarction. METHODS:Data were abstracted from a single center prospective stroke database over 18 months and included all patients with ischemic stroke who underwent contrast-enhanced computerized tomography (CT) of the abdomen and pelvis for clinical purposes within 1 year of stroke. The primary predictor was troponin concentration ≥.1 ng/mL. The primary outcome was visceral infarct (renal and/or splenic) on CT abdomen and pelvis. Univariate and multivariable logistic regression models were used to estimate the odds ratio and 95% confidence intervals (OR, 95% CI) for the association of troponin with visceral infarction. RESULTS:Of 1233 patients with ischemic stroke, 259 patients had a qualifying visceral CT. Serum troponin level on admission was measured in 237 of 259 patients (93.3%) and 41 of 237 (17.3%) had positive troponin. There were 25 patients with visceral infarcts: 16 renal, 7 splenic, and 2 both. In univariate models, patients with a positive troponin level (versus negative) were more likely to have visceral infarcts (39.1% [9/23] versus 15.0% [32/214], P = .008) and this association persisted in multivariable models (adjusted OR 3.83; 95% CI 1.42-10.31, P = .006). CONCLUSIONS:In ischemic stroke patients, elevated serum troponin levels may help identify patients with visceral infarcts. This suggests that troponin in the acute stroke setting is a biomarker of embolic risk. Larger studies with systematic visceral imaging are needed to confirm our findings.

PURPOSE: To create standard T2 map profiles from the entire femoral cartilage of healthy volunteers in order to assess regional variations using an angular and layer-dependent approach. MATERIALS AND METHODS: Twenty healthy knees were evaluated using 3T sagittal images of a T2 mapping sequence. Manual segmentation of the entire femoral cartilage was performed slice-by-slice by two raters using MatLab. Inter- and intrarater reliabilities were calculated using intraclass correlation coefficient (ICC) and Bland-Altman analysis. T2 values were analyzed with respect to specific locations (medial condyle, trochlea, and lateral condyle), angles to B0 , and layers of cartilage (whole, deep, and superficial). RESULTS: Inter- and intrarater reliability obtained from the entire femoral cartilage was excellent (ICC = 0.84, 0.86, respectively). The ICCs around the trochlea were lower than those of the medial and lateral condyle. Both the inter- and intrarater Bland-Altman plots indicated larger differences in pixel count are seen as the size of the angular segment becomes larger. T2 values were significantly higher in the superficial layer compared to the deep layer at each femoral compartment (P < 0.001). A magic angle effect was clearly observed, especially within the whole and deep layer over the medial and lateral femoral condyles, except for the superficial layer at the medial condyle. CONCLUSION: The normal T2 map profiles of the entire femoral cartilage showed variations in ICCs by location and in T2 values by angles and layers. These profiles can be useful for diagnosis of early cartilage degeneration in a specific angle and layer of each condyle and trochlea. J. MAGN. RESON. IMAGING 2015.

IMPORTANCE: Psychiatric diagnoses are currently distinguished based on sets of specific symptoms. However, genetic and clinical analyses find similarities across a wide variety of diagnoses, suggesting that a common neurobiological substrate may exist across mental illness. OBJECTIVE: To conduct a meta-analysis of structural neuroimaging studies across multiple psychiatric diagnoses, followed by parallel analyses of 3 large-scale healthy participant data sets to help interpret structural findings in the meta-analysis. DATA SOURCES: PubMed was searched to identify voxel-based morphometry studies through July 2012 comparing psychiatric patients to healthy control individuals for the meta-analysis. The 3 parallel healthy participant data sets included resting-state functional magnetic resonance imaging, a database of activation foci across thousands of neuroimaging experiments, and a data set with structural imaging and cognitive task performance data. DATA EXTRACTION AND SYNTHESIS: Studies were included in the meta-analysis if they reported voxel-based morphometry differences between patients with an Axis I diagnosis and control individuals in stereotactic coordinates across the whole brain, did not present predominantly in childhood, and had at least 10 studies contributing to that diagnosis (or across closely related diagnoses). The meta-analysis was conducted on peak voxel coordinates using an activation likelihood estimation approach. MAIN OUTCOMES AND MEASURES: We tested for areas of common gray matter volume increase or decrease across Axis I diagnoses, as well as areas differing between diagnoses. Follow-up analyses on other healthy participant data sets tested connectivity related to regions arising from the meta-analysis and the relationship of gray matter volume to cognition. RESULTS: Based on the voxel-based morphometry meta-analysis of 193 studies comprising 15 892 individuals across 6 diverse diagnostic groups (schizophrenia, bipolar disorder, depression, addiction, obsessive-compulsive disorder, and anxiety), we found that gray matter loss converged across diagnoses in 3 regions: the dorsal anterior cingulate, right insula, and left insula. By contrast, there were few diagnosis-specific effects, distinguishing only schizophrenia and depression from other diagnoses. In the parallel follow-up analyses of the 3 independent healthy participant data sets, we found that the common gray matter loss regions formed a tightly interconnected network during tasks and at resting and that lower gray matter in this network was associated with poor executive functioning. CONCLUSIONS AND REVELANCE: We identified a concordance across psychiatric diagnoses in terms of integrity of an anterior insula/dorsal anterior cingulate-based network, which may relate to executive function deficits observed across diagnoses. This concordance provides an organizing model that emphasizes the importance of shared neural substrates across psychopathology, despite likely diverse etiologies, which is currently not an explicit component of psychiatric nosology.