Faculty Bibliography

PURPOSE: To determine the fractional brain tissue volume changes in the gray matter and white matter of patients with relapsing-remitting multiple sclerosis (MS) and to correlate these measurements with clinical disability and total lesion load. MATERIALS AND METHODS: Thirty patients with relapsing-remitting MS and 25 healthy control subjects underwent magnetic resonance imaging. Fractional brain tissue volumes (tissue volume relative to total intracranial volume) were obtained from the total segmented gray matter and white matter in each group and were analyzed. RESULTS: The fractional volume of white matter versus that of gray matter was significantly lower (-6.4%) in patients with MS (P <.0001) than in control subjects. Neither gray matter nor white matter fractional volume measurements correlated with clinical disability in the patients with MS. CONCLUSION: Loss of brain parenchymal volume in patients with relapsing-remitting MS is predominantly confined to white matter. Analysis of fractional brain tissue volumes provides additional information useful in characterizing MS and may have potential in evaluating treatment strategies

PURPOSE: This study was designed to test the feasibility of conducting routine quality assessment within community medical oncology practices. DESCRIPTION OF STUDY: Eleven medical oncologists practicing within the Fox Chase Network were surveyed over an 8-month period, using a standardized 10-item checklist. Eight of the items (ie, board certification, continuing education, office procedure manual for chemotherapy, chemotherapy flow sheets, body surface area calculations, adherence to guidelines for follow-up of breast cancer, adjuvant hormones in women with estrogen receptor-positive breast cancer, and patient satisfaction survey) were chosen because they measure structural and process variables particularly relevant to the high-volume clinical services seen in private practice oncology. The authors also calculated two rates (protocol accrual and neutropenic complications of chemotherapy) to test as putative indicators of quality. RESULTS: The authors found a high level of both physician interest in developing the audit measures and compliance with the survey process. Overall quality of care, as measured by structure and process variables, was excellent with negligible internal variability. Derived rates of protocol accrual (0.003-0.373; mean 0.11, SD 0.11) and neutropenic sepsis (0.004-0.014; mean 0.007, SD 0.004) show considerable variability, however, and are only minimally correlated (r= -.36). These are both potential indicators of quality that should be further evaluated. CLINICAL IMPLICATIONS: The authors have demonstrated the feasibility of conducting quality assessment within private medical oncology practices and have identified two easily calculated rates that merit further study as potential indicators of quality

Recent improvements in our understanding of drug metabolism have led to the development of anticancer therapies that accommodate patient differences in drug tolerance. Such methods adjust the dose level according to measurable patient characteristics in order to obtain a target drug exposure. This paper describes the utilization of a patient specific dosing scheme in the statistical design of a phase I clinical trial involving patients with advanced adenocarcinomas of gastrointestinal origin. During the trial, dose levels were adjusted according to each patient's pretreatment concentration of an antibody that was shown in preclinical testing to moderate the effect of the agent under investigation. The design of the trial permitted a continual adjustment of the model used to tailor the dose to each patient's individual needs

CCND1 gene amplification and cyclin D1 protein overexpression are indicators for poor prognosis in invasive head and neck carcinomas. Increased CCND1 gene dosage is a more sensitive prognostic factor than protein overexpression as evaluated by conventional immunohistochemical techniques. Qualitative immunohistochemistry cannot distinguish cyclin D1 overexpression accompanied by amplification of the CCND1 gene from overexpression associated with normal CCND1 gene copy number. To improve the sensitivity of cyclin D1 protein determination, we applied quantitative techniques of image analysis to evaluate cyclin D1 in 54 head and neck carcinomas. There was a significantly higher rate of occurrence of adverse events (P = 0.043) among patients with CCND1 gene amplification than among those without gene amplification. There was a strong association between CCND1 gene amplification (as detected by Southern blot analysis) and the highest nuclear score (by image cytometry of the immunostained tumor sections). The predominance of cells in the lowest nuclear score category was significantly associated with normal copy number (P = 0.005). Conversely, the highest nuclear score was a significant predictor of gene dosage (P = 0.02). Similarly, high nuclear score was a good predictor of death as the final outcome of the disease (P = 0.01). Although somewhat less accurate than Southern blotting, image cytometry of immunohistochemical cyclin D1 stain appears to be a promising tool that could be useful for other tumor marker expression studies

BACKGROUND AND PURPOSE: Gray matter may be affected by multiple sclerosis (MS), a white matter disease. Magnetization transfer ratio (MTR) is a sensitive and quantitative marker for structural abnormalities, and has been used frequently in the imaging of MS. In this study, we evaluated the amount of MTR of gray matter among patients with relapsing-remitting MS and healthy control subjects as well as the correlation between gray matter MTR abnormality and neurologic disability associated with relapsing-remitting MS. METHODS: We obtained fast spin-echo dual-echo and magnetization transfer (with and without MT saturation pulses) images from eighteen patients with relapsing-remitting MS and 18 age-matched healthy control subjects. Gray matter was segmented using a semiautomated system. Gray matter MTR histogram parameters, Kurtzke Expanded Disability Status Scale (EDSS), total T2 lesion volume, and gray matter volumes were obtained for statistical analysis. RESULTS: A significant difference was found in gray matter MTR between patients with relapsing-remitting MS and healthy subjects (mean and median). Gray matter MTR histogram normalized peak heights in patients inversely correlated with EDSS (r = -0.65, P =.01). There was also an inverse correlation between mean MTR of gray matter and total T2 lesion volume. CONCLUSION: The MTR of gray matter significantly differed between patients with relapsing-remitting MS and healthy control subjects, suggesting that MS is a more diffuse disease affecting the whole brain, and neuronal damage accumulates in step with T2 lesion volume. Our finding of the relationship between gray matter MTR and EDSS indicates that measurement of gray matter abnormality may be a potentially useful tool for assessing clinical disability in MS

OBJECTIVE: To determine the relationship between gadolinium-enhancing lesions and changes in whole brain parenchymal volume in patients with relapsing-remitting MS, and to test the hypothesis that gadolinium enhancement is a predictor of whole brain atrophy. METHODS: Twenty-four patients with clinically definite MS were imaged over 2 years. A computer-assisted segmentation technique based on high-resolution MRI was used to quantify gadolinium-enhancing T1 lesion volume and brain parenchyma and CSF volumes. Percent brain parenchymal volume (PBV) relative to the total intracranial volume was calculated, and changes in PBV were used to represent the degree of whole brain atrophy over 2 years. RESULTS: PBV at baseline was dependent on duration of MS, and a significant decrease in PBV was observed over the course of the study. Changes in enhanced T1 lesion load failed to correlate with changes in PBV, and multiple regression analyses determined that enhanced T1 lesion load at baseline was not a significant predictor of subsequent change in PBV. CONCLUSIONS: MR visible inflammation as demonstrated by enhanced T1 lesions is not a significant factor in the pathogenesis of whole brain atrophy in relapsing-remitting MS, suggesting that a more global pathologic process is responsible for the loss of brain parenchymal volume

OBJECTIVE: To evaluate the efficacy of glatiramer acetate (GA, Copaxone; Teva Pharmaceutical Industries, Ltd., Petah Tiqva, Israel) by MRI-based measures in patients with relapsing-remitting (RR) MS. METHODS: Twenty-seven patients with clinically definite RR-MS were treated with either 20 mg of GA by daily subcutaneous self-injection (n = 14) or placebo (n = 13) for approximately 24 months. Axial dual-echo fast-spin-echo T2-weighted images and T1-weighted images before and after gadolinium (Gd) were acquired at 1.5 tesla and transferred into an image processing computer system. The main outcome measures were the number of Gd-enhanced T1 and T2 lesions and their volume as well as brain parenchyma volume. RESULTS: The values of age, disease duration, Expanded Disability Status Scale (EDSS) score, the number of T1- and T2-weighted lesions, and their volume were similar between GA- and placebo-receiving groups at the entry of this study. There was a decrease in the number of T1-enhanced lesions (p = 0.03) and a significant percent annual decrease of their volume in GA recipients compared with those of placebo recipients. There were no significant differences between changes in the two groups in the number of T2 lesions and their volume. The loss of brain tissue was significantly smaller in the GA group compared with that of the placebo group. CONCLUSIONS: These results show that GA treatment may decrease both lesion inflammation and the rate of brain atrophy in RR-MS

OBJECTIVE: To quantitate the extent of neuronal cell loss in MS via the whole brain's N-acetylaspartate (NAA) concentration (WBNAA). METHODS: Because NAA is assumed to be present only in neuronal cell bodies and their axons, we measured WBNAA as a marker for viable neurons in 12 patients (9 women and 3 men, 26 to 53 years of age) suffering from relapsing-remitting (RR) MS for at least 5 years and compared them with 13 age- and sex-matched normal controls. Total brain NAA was determined with proton MR spectroscopy, and WBNAA was obtained by dividing it by the total brain volume, calculated from high resolution MRI. RESULTS: The WBNAA of the RR MS patients was lower than their matched controls (p<0.005). This difference was greater among older than younger subjects. The linear prediction equations of WBNAA with age indicate a faster, x10, decline in the patients, approximately 0.8% per year of age (p = 0.022). CONCLUSION: The age-dependent decrease of whole brain N-acetylaspartate (WBNAA) in the patients suggests that progressive neuronal cell loss is a cardinal feature of this disease. WBNAA offers a quick, highly reproducible measure of disease progression and may be an important marker of treatment efficacy in MS as well as other neurodegenerative diseases