Roger L. Priore

Neuropsychological effects of interferon β-1a in relapsing multiple sclerosis

Cognitive dysfunction is common in multiple sclerosis (MS), yet few studies have examined effects of treatment on neuropsychological (NP) performance. To evaluate the effects of interferon β‐1a (IFNβ‐1a, 30 μg administered intramuscularly once weekly [Avonex]) on cognitive function, a Comprehensive NP Battery was administered at baseline and week 104 to relapsing MS patients in the phase III study, 166 of whom completed both assessments. A Brief NP Battery was also administered at 6‐month intervals. The primary NP outcome measure was 2‐year change on the Comprehensive NP Battery, grouped into domains of information processing and learning/memory (set A), visuospatial abilities and problem solving (set B), and verbal abilities and attention span (set C). NP effects were most pronounced in cognitive domains vulnerable to MS: IFNβ‐1a had a significant beneficial effect on the set A composite, with a favorable trend evident on set B. Secondary outcome analyses revealed significant between‐group differences in slopes for Brief NP Battery performance and time to sustained deterioration in a Paced Auditory Serial Addition Test processing rate, favoring the IFNβ‐1a group. These results support and extend previous observations of significant beneficial effects of IFNβ‐1a for relapsing MS. Ann Neurol 2000;48:885–892

Diet and alcohol consumption and lung cancer risk in the New York State Cohort (United States)

The relationship between diet and alcohol and lung cancer was evaluated among participants of the New York State Cohort (United States),comprising 27,544 men (395 cases) and 20,456 women (130 cases) who completed a brief mailed questionnaire in 1980. Participants were followed up through1987 with the assistance of the New York State Department of Healths Vital Statistics Section and Cancer Registry. Among men, inverse relationships with vitamin C, folate, and carotenoids, and positive associations with total fat, monounsaturated and saturated fat were observed after adjusting for age, education, cigarettes/day, years smoking, and total energy intake. The relationships observed with folate and saturated fat were stronger for heavy smokers. Also, the effect of folate, total fat, and monounsaturated fat seemed to be limited to squamous cell carcinomas. We found no indication that cholesterol or polyunsaturated fat was associated with lung cancer. Diet did not appear to exert a major role on lung cancer risk among women. Although diet modification should never be considered a substitute for smoking cessation, its role as an additional strategy in lung cancer prevention deserves attention.

Brain MRI lesions and atrophy are related to depression in multiple sclerosis

It is unclear whether brain MRI lesions are associated with depression in multiple sclerosis (MS). Neurological dysfunction in depressed (n = 19) and non-depressed (n = 29) MS patients was rated by expanded disability status scale (EDSS). EDSS was weakly predictive of the presence of (p = 0.03) and severity of (p = 0.01) depression. After correcting for EDSS, the presence of depression was predicted by superior frontal and superior parietal hypointense T1 lesions (p <0.01); the severity of depression was predicted by superior frontal, superior parietal and temporal T1 lesions, lateral and third ventricular enlargement, and frontal atrophy (p <0.01). Depression was not related to bright T2 lesions or enhancement. We conclude that atrophy and cortical–subcortical disconnection due to frontal and parietal white matter destructive lesions may contribute to depression in MS.

Diet and cancer of the esophagus

The reported dietary, alcohol consumption and smoking habits of 147 Roswell Park Memorial Institute white male patients diagnosed with cancer of the esophagus were compared with the reports of 264 white males of comparable ages with diagnoses other than cancer. Overall frequency of vegetable an fruit consumption was associated with lower risk; persons reporting fruit and/or vegetable consumption 31-40 times a month had significantly greater risk than those who reported consumption 81 times a month or more. Calculated indexes of vitamin A and vitamin C intake were similarly related to reduction in risk. Dose-response gradients were observed for frequency of vegetable and/or fruit consumption, as well as for vitamin A and C intake. The putative protective effect of vegetable and fruit intake remained evident after controlling for its possible association with smoking and drinking. Previously reported associations of smoking, alcohol use and social class, as measured by type of occupation, were replicated in these data. The findings of this investigation in instances of colon, lung, bladder, oral, and laryngeal cancers, and with evidence of tumor inhibition by vegetable properties in animals. Interpretation of the findings is limited by the difficulties of retrospective assessment of dietary intake and by possible confounding by other factors known to be related to esophageal cancer.

Thromboembolism Prophylaxis in Chronic Atrial Fibrillation Practice Patterns in Community and Tertiary-Care Hospitals

BACKGROUND AND PURPOSE By 1992, several prospective trials established the efficacy of anticoagulation (AC) and to some extent antiplatelet (AP) agents in the prevention of stroke in the setting of atrial fibrillation (AF). The objective of this study was to determine whether practice patterns in AF stroke prophylaxis reflect the findings of clinical trials and whether stroke prophylaxis in AF differs between community hospitals and tertiary teaching hospitals. METHODS Retrospectively, 1250 hospital charts were reviewed. After patients who had undergone recent surgery, received treatment for malignancy, or were not in chronic AF on discharge were eliminated, 651 remaining records were analyzed for the presence of 26 clinical factors influencing the selection of thromboembolism prophylaxis. Descriptive statistics and logistic regression were used to analyze the association between clinical and demographic factors and the decision to treat with AC, AP, or no specific antiembolic therapy. RESULTS Of the 651 patients in AF, 273 (42%) received noemboli prophylaxis while 219 (34%) were treated with AC (warfarin), 146 (22%) were treated with AP, and 13 (2%) received both agents. Patients discharged in AF from community hospitals were significantly less likely to be treated with either AC or AP agents than patients discharged from tertiary centers. A strong bias against thromboembolism prophylaxis with either AC or AP agents in AF existed with age over 45 years. Multivariate logistic regression indicated that the decision to treat was associated only with the presence of prosthetic valve, history of prior stroke, mitral disease, and absence of a recent gastrointestinal bleed or occult blood in stool. Even after adjustment for these factors, a significant bias against treatment with either AC or AP agents with advancing age and discharge from community hospitals remained. CONCLUSIONS Thromboembolism prophylaxis with either AC or AP agents is underutilized in the setting of AF. Furthermore, factors known to increase the risk of embolization in AF such as age, hypertension, diabetes, and heart disease were not associated with decisions to treat with either AP or AC agents. This study suggests that the use of clinical guidelines suggested by trials of thromboembolism prophylaxis in AF could reduce the incidence of stroke.

A multifactorial intervention to reduce prevalence of delirium and shorten hospital length of stay.

Objectives: To improve outcomes for cognitively impaired and delirious older adults.

A phase III trial of intramuscular recombinant interferon beta as treatment for exacerbating-remitting multiple sclerosis: design and conduct of study and baseline characteristics of patients

The design and conduct of a randomized, double-blinded, placebo-controlled, multicenter, phase III study of recombinant interferon beta-1a (IFN-β-1a) as treatment for exacerbating-remitting MS are described, as are baseline characteristics of the study population. The purpose of the study was to determine if 6.0 × 106 IU (30 μg) of IFN-β-1a, administered by weekly intramuscular (i.m.) injections, was effective in delaying the onset of sustained disability. The primary outcome measure was time to onset of treatment failure, defined as a worsening on the Kurtzke Expanded Disability Status Scale (EDSS) of greater than or equal to 1.0 point compared with baseline, persisting for at least 6 months. An intent-to-treat design was used. The primary outcome measure was analyzed using the Mantel-Cox log-rank statistic and Kaplan-Meier survival curves. Secondary outcomes included quantitative measures of upper and lower extremity function, neuropsychological test performance, functional and quality of life assessments and several measures derived from annual brain MRI studies. Entry criteria included prestudy exacerbation rates of at least 0.67 per year and EDSS scores of 1.0–3.5. A total of 301 MS patients were randomly assigned to receive weekly i.m. injections of IFN-β-1a or placebo. The average age of the study population at entry was 37 years; 92% were Caucasian and 73% were women. The mean prestudy disease duration was 6.5 years, mean prestudy exacerbation rate was 1.2 per year and the mean EDSS score was 2.3. The randomization yielded well-balanced treatment arms. Various aspects of the study are discussed, including: (1) the decision to focus study design on sustained disability; (2) the rationale for the treatment regimen; (3) measures taken to assure the reliability of the primary outcome measure; and (4) a description of the secondary outcome measures.

Genital cancer in wives of penile cancer patients

We identified the wives or ex‐wives of 227 males of the 256 reported with cancer of the penis to the New York State Cancer Registry from Upstate New York from 1960–64. Utilizing the Registry, death certificates, hospital and physician records, we ascertained those wives who developed cancer at any site from 1951–1975. We generated expected numbers of cases of cancer at each site by applying the age‐specific incidence rates experienced by women of a specific age in a specific year designated by the age of the wife of the index case in each year, estimating withdrawals from age‐specific death rates. Thus, our expected numbers are based on the experience of the women in Upstate New York with traits like those of spouses of the men in the same population with cancer of the penis. We found significantly more cases of cancer of the cervix than expected. This was not true for other sites of cancer.

Cerebrospinal fluid abnormalities in a phase III trial of Avonex® (IFNβ-1a) for relapsing multiple sclerosis

Abstract Background and objective : This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNβ-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827),a (Avonex®, Biogen). The clinical trial demonstrated that IFNβ-1a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNβ-1a therapy on these CSF abnormalities. Methods : CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. Results : (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd-enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNβ-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. Conclusions : The current study documents significant reductions in CSF WBC counts in patients treated with IFNβ-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.BACKGROUND AND OBJECTIVE This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNbeta-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827),a (Avonex , Biogen). The clinical trial demonstrated that IFNbeta-1a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNbeta-1a therapy on these CSF abnormalities. METHODS CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. RESULTS (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd-enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNbeta-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. CONCLUSIONS The current study documents significant reductions in CSF WBC counts in patients treated with IFNbeta-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.

Prospective Evaluation of the Ottawa Ankle Rules in a University Sports Medicine Center With a Modification to Increase Specificity for Identifying Malleolar Fractures

In a sports medicine center, we prospectively evaluated the Ottawa Ankle Rules over 1 year for their ability to identify clinically significant ankle and midfoot fractures and to reduce the need for radiography. We also developed a modification to improve specificity for malleolar fracture identification. Patients with acute ankle injuries ( 10 days old) had the rules applied and then had radiographs taken. Sensitivity, specificity, and the potential reduction in the use of radiography were calculated for the Ottawa Ankle Rules in 132 patients and for the new “Buffalo” rule in 78 of these patients. There were 11 clinically significant fractures (fracture rate, 8.3% per year). In these 132 patients, the Ottawa Ankle Rules would have reduced the need for radiography by 34%, without any fractures being missed (sensitivity 100%, specificity 37%). In 78 patients, the specificity for malleolar fracture for the new rule was significantly greater than that of the Ottawa Ankle Rules malleolar rule (59% versus 42%), sensitivity remained 100%, and the potential reduction in the need for radiography (54%) was significantly greater. The Ottawa Ankle Rules could significantly reduce the need for radiography in patients with acute ankle and midfoot injuries in this setting without missing clinically significant fractures. The Buffalo modification could improve specificity for malleolar fractures without sacrificing sensitivity and could significantly reduce the need for radiography.