John A. Jesberger

Brain Activation During Silent Word Generation Evaluated with Functional MRI

This is a study of word generation during functional MRI (fMRI). Eleven normal healthy subjects were instructed to generate words covertly, (i.e., silently) that began with particular letters. Images were acquired on a conventional 1.5T scanner at three contiguous axial planes encompassing language-related areas of the temporal and frontal lobe. The data were analyzed at the level of a Talairach box, after individually fitting the proportional Talairach grid system to each slice. The main variable of interest was the number of activated pixels within a Talairach box. Boxes with a significant increase in the proportion of activated pixels were located in three regions of the left neocortex: (1) Brodmann areas 44 and 45 in the dorsolateral frontal cortex (Brocas area), (2) areas 21 and 37 in the temporal cortex, (3) and the striate/extrastriate cortex (areas 17 & 18). The results are discussed in terms of a cognitive model of word generation and are compared, in detail, with the results of prior relevant imaging studies.

A magnetic resonance imaging study of thalamic area in adolescent patients with either schizophrenia or bipolar disorder as compared to healthy controls

The purpose of this study was to compare thalamic size in adolescent patients with either schizophrenia or bipolar disorder and healthy controls. T2-weighted axial magnetic resonance images were used to manually define the area of the thalamus for 20 schizophrenia patients, 15 bipolar patients and 16 normal control subjects, all of whom were adolescents. Two orthogonal planned contrasts were tested: Contrast 1, patients with schizophrenia vs. patients with bipolar disorder; and Contrast 2, both patient groups taken as a single group compared to controls. Contrast 1 was not statistically significant for right or left thalamic area. Contrast 2 was statistically significant and indicated reductions in thalamic area in the patients as compared to controls. The same pattern of results emerged after adjustment for total brain volume. Our results indicate that thalamic abnormalities reported in adult schizophrenic and bipolar patients are also observed in adolescent patients. Our findings also add to the evidence implicating the thalamus in the pathophysiology of schizophrenia and bipolar disorder.

Quantitative assessment of smooth pursuit gain and catch-up saccades in schizophrenia and affective disorders

The smooth pursuit responses to 5 degrees and 20 degrees/sec constant-velocity stimuli were recorded from 23 patients with schizophrenia, 16 affective disorder patients, and 21 normals using low-noise infrared oculography. Pursuit gain, catch-up saccade (CUS) rate and amplitude, and their interrelationships were examined. Gain in the schizophrenic patients was reduced only at 20 degrees/sec, but for both patient groups, CUS rate at 5 degrees/sec was significantly lower than in normals. Using CUS rate at 20 degrees/sec, the patient groups could be distinguished from each other (the rate for schizophrenic patients being highest, and the rate for affectives the lowest) but neither differed significantly from normals. The diagnostic groups did not differ significantly in mean CUS amplitude, although there was a trend for patients to have larger saccades. Gain-CUS rate correlation was strong in normals but reduced or absent in both patient groups. These results indicate that the ocular motor systems of patients with schizophrenia and affective disorders process eye position error abnormally.

An MRI study of adolescent patients with either schizophrenia or bipolar disorder as compared to healthy control subjects

BACKGROUND There are few imaging studies in adolescent patients with either schizophrenia or bipolar disorder. Such studies are of interest because adolescents may have a more severe illness and neurodevelopmental events may have a greater role in their pathophysiology. METHODS We compared 20 patients with schizophrenia and 15 patients with bipolar disorder (10 to 18 years) to 16 normal adolescents on magnetic resonance imaging (MRI) measures of intracranial volume and ventricular and sulcal enlargement. Two planned comparison contrasts were employed, one comparing the two patient groups to each other (contrast 1), and one comparing both patient groups combined to control subjects (contrast 2). RESULTS None of the contrast 1 comparisons (schizophrenia vs bipolar) were statistically significant. Contrast 2 comparisons (control subjects vs patients) were statistically significant for intracranial volume (reduced in patients) as well as frontal and temporal sulcal size (increased in patients). CONCLUSIONS The patient groups were not statistically significantly different from each other on any measure. The combined patient groups were different from control subjects on intracranial volume and frontal and temporal sulcal size. Also, there was evidence for ventricular enlargement, after removal of a control subject with an extreme value. These findings indicate that the same abnormalities noted in adult populations are present in adolescents.

A vasculature-targeting regimen of preoperative docetaxel with or without bevacizumab for locally advanced breast cancer: Impact on angiogenic biomarkers

Purpose: Taxanes have effects on angiogenesis causing difficulties in separating biological effects of chemotherapy from those due to angiogenesis inhibitors. This randomized phase II trial was designed to evaluate the additional biomarker effect on angiogenesis when bevacizumab is added to docetaxel. Experimental Design: Patients with inoperable breast cancer were randomized to either 2 cycles of preoperative docetaxel (D) 35 mg/m2 i.v. weekly for 6 weeks, followed by a 2-week break; or docetaxel with bevacizumab 10 mg/kg i.v. every other week for a total of 16 weeks (DB). Plasma and serum markers of endothelial damage, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and tumor microvessel density were assessed before treatment and at the end of each preoperative cycle. Results: Forty-nine patients were randomized (DB, 24; D, 25). There was no difference in overall clinical response, progression-free survival, or overall survival. Vascular endothelial growth factor increased during treatment; more so with DB (P < 0.0001). Vascular cell adhesion molecule-1 (VCAM-1) also increased (P < 0.0001); more so with DB (P = 0.069). Intercellular adhesion molecule increased (P = 0.018) and E-selectin decreased (P = 0.006) overall. Baseline levels of VCAM-1 and E-selectin correlated with clinical response by univariate analysis. DCE-MRI showed a greater decrease in tumor perfusion calculated by initial area under the curve for the first 90 seconds in DB (P = 0.024). DCE-MRI also showed an overall decrease in tumor volume (P = 0.012). Conclusion: Bevacizumab plus docetaxel caused a greater increase in vascular endothelial growth factor and VCAM-1, and a greater reduction in tumor perfusion by DCE-MRI compared with docetaxel. Clinical outcomes of inoperable breast cancer were predicted by changes in VCAM-1 and E-selectin.

Determining and optimizing the precision of quantitative measurements of perfusion from dynamic contrast enhanced MRI

To examine the sensitivity of quantitative dynamic contrast enhanced MRI (DCE‐MRI) perfusion maps to errors in the various source images and to determine optimal imaging parameters for reducing this sensitivity.

Inflammatory breast cancer as a model disease to study tumor angiogenesis : Results of a phase IB trial of combination SU5416 and doxorubicin

Purpose: We used inflammatory breast cancer (IBC) as a model disease to investigate biological changes associated with an antiangiogenesis agent, SU5416, combined with doxorubicin. Experimental Design: Patients with stage IIIB or IV IBC were treated neoadjuvantly with the combination of SU5416 and doxorubicin for induction therapy. The dose of SU5416 (administered on days 1 and 4, every 3 weeks) and doxorubicin (administered on day 1 every 3 weeks) were escalated in cohorts of three patients starting at 110 and 60 mg/m2, respectively, for a total of five cycles leading up to mastectomy. Patients underwent serial assessment (pharmacokinetic sampling, biopsy of breast, tumor blood flow dynamic contrast-enhanced magnetic resonance imaging, plasma angiogenesis, and endothelial cell damage markers) prior to treatment, at the end of cycles no. 2 and no. 5, and after mastectomy. Results: Eighteen patients were enrolled; neutropenia was dose-limiting, and overall median survival was not reached (50 months of study follow-up). Four patients (22%) experienced congestive heart failure, which resolved and were likely attributable to a smaller volume of distribution and higher Cmax of doxorubicin in combination with SU5416. We did observe a significant decline in tumor blood flow using Kep calculated by Brix (pretreatment versus post-cycle no. 5; P = 0.033), trend for a decline in tumor microvessel density after treatment, and low baseline levels of soluble intracellular adhesion molecule were associated with improved event-free survival. Conclusions: This study showed evidence of an unfavorable cardiac interaction between SU5416 and doxorubicin, which prohibits further investigation of this combination. However, this study supports the importance of using IBC as a model for investigating angiogenesis inhibitors.

Phase II trial of neoadjuvant docetaxel with or without bevacizumab in patients with locally advanced breast cance.

727 Background: The anti-angiogenic agent, bevacizumab (rhuMAbVEGF) is a humanized monoclonal antibody against VEGF which, when combined with docetaxel in preclinical models, results in synergistic suppression of capillary vessel formation. Based on these data, a randomized phase II trial was developed to evaluate the vascular effects on tumor regression with combination bevacizumab/docetaxel vs. docetaxel in the treatment of locally advanced breast cancer. METHODS 33 patients (pts) were randomized to receive neoadjuvant therapy with bevacizumab (10 mg/kg qowk) and docetaxel (two 8-week cycles of 35 mg/m2 weekly x 6 with a 2 wk break) or docetaxel alone. Eligible pts had locally unresectable breast cancer with or without metastasis. Pts who responded underwent definitive surgery, radiation, 4 cycles of adjuvant conventional Adriamycin/cyclophosphamide, followed by tamoxifen (if ER/PR+). RESULTS 26 pts completed pre-operative treatment. 3 pts with inflammatory breast cancer were not operable at the conclusion of therapy because of residual disease. The median number of pathologically + lymph nodes (ln) was 1 (range 0-16); 40% were ln negative. The median size of residual tumor was 3.2cm (range 0-14cm). Toxicity included: grade 4 neutropenia-4; grade 3: anorexia-3; GI bleed-1; stomatitis-3; neuropathy-1; wound healing-1. There was no change in LVEF, no hypertension, protienuria, or thrombosis. Preliminary analysis of correlative studies suggests a reduction in tumor Kep by DCE-MRI and a reduction of tumor microvessel density. CONCLUSIONS Neoadjuvant therapy for locally advanced breast cancer using docetaxel with or without bevacizumab is well tolerated and effective. This study requires a total of 60 pts before an analysis can be made of a treatment difference in vascular and disease response. Laboratory correlatives evaluating effects on tumor vasculature are ongoing. (Sponsored by grants: K23CA 87725-01, M01 RR 00080, UO1 CA 62502, P30 CA43703S NCI/Avon) No significant financial relationships to disclose.

Intramyocellular lipid content and insulin sensitivity are increased following a short-term low-glycemic index diet and exercise intervention

The relationship between intramyocellular (IMCL) and extramyocellular lipid (EMCL) accumulation and skeletal muscle insulin resistance is complex and dynamic. We examined the effect of a short-term (7-day) low-glycemic index (LGI) diet and aerobic exercise training intervention (EX) on IMCL and insulin sensitivity in older, insulin-resistant humans. Participants (66 ± 1 yr, BMI 33 ± 1 kg/m(2)) were randomly assigned to a parallel, controlled feeding trial [either an LGI (LGI/EX, n = 7) or high GI (HGI/EX, n = 8) eucaloric diet] combined with supervised exercise (60 min/day, 85% HR(max)). Insulin sensitivity was determined via 40 mU·m(-2)·min(-1) hyperinsulinemic euglycemic clamp and soleus IMCL and EMCL content was assessed by (1)H-MR spectroscopy with correction for fiber orientation. BMI decreased (kg/m(2) -0.6 ± 0.2, LGI/EX; -0.7 ± 0.2, HGI/EX P < 0.0004) after both interventions with no interaction effect of diet composition. Clamp-derived insulin sensitivity increased by 0.91 ± 0.21 (LGI/EX) and 0.17 ± 0.55 mg·kg(-1)·min(-1) (HGI/EX), P = 0.04 (effect of time). HOMA-IR was reduced by -1.1 ± 0.4 (LGI/EX) and -0.1 ± 0.2 (HGI/EX), P = 0.007 (effect of time), P = 0.02 (time × trial). Although both interventions increased IMCL content, (Δ: 2.3 ± 1.3, LGI/EX; 1.4 ± 0.9, HGI/EX, P = 0.03), diet composition did not significantly effect the increase. However, the LGI/EX group showed a robust increase in the [IMCL]/[EMCL] ratio compared with the HGI/EX group (Δ: 0.5 ± 0.2 LGI/EX vs. 0.07 ± 0.1, P = 0.03). The LGI/EX group also demonstrated greater reductions in [EMCL] than the HGI/EX group (Δ: -5.8 ± 3.4, LGI/EX; 2.3 ± 1.1, HGI/EX, P = 0.03). Changes in muscle lipids and insulin sensitivity were not correlated; however, the change in [IMCL]/[EMCL] was negatively associated with the change in FPI (r = -0.78, P = 0.002) and HOMA-IR (r = -0.61, P = 0.03). These data suggest that increases in the IMCL pool following a low glycemic diet and exercise intervention may represent lipid repartitioning from EMCL. The lower systemic glucose levels that prevail while eating a low glycemic diet may promote redistribution of lipid stores in the muscle.

Clinical evaluation of CAIPIRINHA: Comparison against a GRAPPA standard

To evaluate image quality when using a CAIPIRINHA sampling pattern in comparison to a standard GRAPPA sampling pattern in patients undergoing a routine three‐dimensional (3D) breathheld liver exam. CAIPIRINHA uses an optimized phase encoding sampling strategy to alter aliasing artifacts in 3D acquisitions to improve parallel imaging reconstruction.