The international collaborative study of maternal phenylketonuria: status report 1994

Neonatal screening for phenylketonuria (PKU) has created a problem as females with PKU are reaching child-bearing age. Surveys have revealed that maternal phenylalanine blood concentrations greater than 1200 μmol/l are associated with fetal microcephaly, congenital heart defects and intrauterine growth retardation. It is estimated that as many as 3000 hyperphenylalaninemic females may be at risk of producing these fetal abnormalities. To examine this problem, the international maternal PKU collaborative study was developed to evaluate the efficacy of a phenylalanine-restricted diet in reducing fetal morbidity. Preliminary findings have indicated that phenylalanine restriction should begin before conception for females with PKU planning a pregnancy. Dietary control should maintain maternal blood phenylalanine levels between 120 and 360 μmol/l and should provide adequate energy, protein, vitamin and mineral intake. Pregnant hyperphenylalaninemic females who achieved metabolic control after conception or by the 10th week of pregnancy had a better offspring outcome than anticipated. The results of 402 pregnancies are reviewed.     

High-dose-rate intraoperative brachytherapy for recurrent colorectal cancer

PURPOSE: Management of locally recurrent colorectal adenocarcinoma represents a significant challenge. Many of these tumors adhere to or invade into vital pelvic structures rendering surgery or external beam radiotherapy (EBRT) as palliative treatment. Therefore, a treatment approach was developed to evaluate the role of high-dose-rate intraoperative brachytherapy (HDR-IORT) and surgery as a component of therapy in the management of locally recurrent colorectal cancer. This is an update of our preliminary report with longer follow-up and larger patient numbers. METHODS AND MATERIALS: Between January 1992 and September 1998, 74 patients with locally recurrent rectal cancer were treated with surgery and HDR-IORT. Additional EBRT was given to 29 patients, and 33 patients received 5-fluorouracil based chemotherapy. All patients underwent complete gross resection, and 21 of 74 had positive microscopic margin. The dose of HDR-IORT ranged from 10 to 18 Gy. RESULTS: With a median follow-up of 22 months, the 5-year local control, distant metastasis disease-free, disease-free, and overall survival rates were 39%, 39%, 23%, and 23%, respectively. The only predictor of improved local control was a negative margin of resection with a 5-year local control rate of 43%, compared to 26% in those with positive margin (p = 0.02). For overall survival, a negative microscopic margin (p = 0.04) and the use of IORT + EBRT (p = 0.04) were significant predictors of improved survival. The incidence of peripheral neuropathy was 16%. CONCLUSION: The results with HDR-IORT in this group of patients are encouraging. Further improvements in local and distant control are still needed.     

Guidelines for using quantitative measures of brain magnetic resonance imaging abnormalities in monitoring the treatment of multiple sclerosis

The change of brain lesion load, measured on T₂-weighted magnetic resonance imaging (MRI) using computer-assisted techniques, is a widely used secondary endpoint for phase III clinical trials in multiple sclerosis (MS). Collections, transfer, and analysis of the electronic data across multiple centers have all proved challenging and give rise to potential errors. However, many new acquisition schemes and postprocessing techniques have been developed; these may reduce scan times and result in better lesion conspicuity or lessen the human interaction needed for data analysis. This review considers many aspects of the use of MRI in clinical trials for MS and provides international consensus guidelines, derived from a task force of the European Magnetic Resonance Networks in Multiple Sclerosis (MAGNIMS) together with a group of North American experts. The main points considered are the organization of correctly powered trials and selection of participating sites; the appropriate choice of pulse sequences and image acquisition protocol given the current state of technology; quality assurance for data acquisition and analysis; accuracy and reproducibility of lesion load assessments; and the potential for the application of quantitative methods to other MRI-derived measures of disease burden.     

Spin-spin relaxation in experimental allergic Encephalomyelitis. Analysis of CPMG data using a non-linear least squares method and linear inverse theory

We have used the CPMG pulse sequence to measure proton T₂ values and water content in spinal cord and brain samples from Hartley guinea pigs inoculated to produce experimental allergic encephalomyelitis (EAE). Relaxation data were fitted using minuit, a non-linear curve fitting routine. Three exponentials provided the best fit to spinal cord data (10 ms (13%), 76 ms (57%), 215 ms (30%)) and two exponentials for brain tissue (10 ms (4%), 92 ms (96%)). Least squares algorithms were also used to analyse the spinal cord data in terms of discrete and smooth distributions of relaxation times. The discrete least squares solutions consisted of three to five isolated spikes between 0.010 and 0.300 s. This type of solution was difficult to interpret in terms of water reservoirs. Smooth solutions consisted of two broad peaks, a small peak with a T₂ near 0.010 s and a larger peak near 0.100 s. The integral ratio of the larger to the smaller peak was 7.092 ± 1.782 for normal tissue, and increased to a maximum of 16 with increasing parenchymal cellular infiltration and demyelination. The short T₂ peak has been assigned to water in the hydration layers of the myelin sheath. The width of the longer T₂ peak was sensitive to tissue heterogeneity. The least squares and smooth distribution analysis models could be used to distinguish samples with extensive parenchymal infiltration from normal tissue, even though only a maximum of 60% of the tissue was affected. The short T₂ component could provide a direct method of measuring intact myelin, which would have a profound effect on the understanding of the evolution of pathology in multiple sclerosis.     

Linoleic acid in multiple sclerosis: Failure to show any therapeutic benefit

We have studied the effect of a dietary supplement with linoleic acid (LA) in 76 patients with MS. We could detect no effect of this supplement on the progression of neurological findings, the relapse rate, or the severity of relapses. We were also able to show that oral supplementation with a linoleic acid preparation would raise the blood level of LA in these patients. We were unable to show that there was any reduction in the linoleic acid blood levels associated with acute relapses of MS during this study.     

CSF electrophoresis: an adaptation using cellulose acetate for the identification of oligoclonal banding.

An adaptation of cellulose acetate electrophoresis for studying concentrated cerebrospinal fluid is described. Two hundred and twenty-one patients have been studied, and the specificity for multiple sclerosis and sub-acute sclerosing panencephalitis is discussed. This has been positive for oligoclonal banding (OB) in 79% of patients with clinically definite multiple sclerosis.     

Regional myocardial dysfunction: evaluation of patients with prior myocardial infarction with fast CT

A prototype ultrafast cine computed tomographic (CT) scanner, designed specifically for cardiac imaging, was used to evaluate a preliminary series of patients with prior myocardial infarction (n = 21) and a control group without coronary artery disease (n = 5). Multilevel 50-msec CT scan exposures were obtained during peripheral intravenous bolus injections of contrast medium. A comparison was made between cine-CT scans and standard left ventriculographic images in assessing segmental left ventricular motion. Results indicate that cine CT, performed at sufficiently rapid speeds (20 scans per second) to allow useful analysis of regional ventricular wall motion, can provide adequate image quality. Analysis of 110 segments revealed a good correlation (90.9%) between the two techniques in characterizing normal from abnormal regional wall motion. Cine CT, based on this initial study, demonstrates considerable potential for evaluating not only cardiac chamber dimensions but also segmental wall dynamics.