James R. Boen

ACYCLOVIR THERAPY FOR MUCOCUTANEOUS HERPES SIMPLEX INFECTIONS IN IMMUNOCOMPROMISED PATIENTS

11 of 24 immunocompromised patients with mucocutaneous herpes simplex virus (HSV) infections were given intravenous acyclovir in a randomised double-blind placebo-controlled study. Patients receiving acyclovir experienced no major adverse effects. The median times to cessation of new lesion formation, lesion crusting, lesion healing, cessation of pain, and termination of viral shedding were shorter in the acyclovir-treated group than in the placebo group. The time-to-event probability curves for the acyclovir and placebo groups were significantly different for cessation of pain (p=0.032) and termination of viral shedding (p=0.004). The median times to termination of viral shedding were also statistically different (p=0.045). Acyclovir seems to be a non-toxic and effective treatment for mucocutaneous HSV infections in immunocompromised patients.

Disease-free intervals after partial ileal bypass in patients with coronary heart disease and hypercholesterolemia: report from the Program on the Surgical Control of the Hyperlipidemias (POSCH)☆

OBJECTIVES We sought to analyze the disease-free intervals and calculate the freedom from atherosclerosis events in the Program on the Surgical Control of the Hyperlipidemias (POSCH). BACKGROUND The POSCH study was a randomized, secondary lipid/atherosclerosis intervention trial that provided strong evidence for reduction in atherosclerosis progression as demonstrated by clinical and arteriographic end points. The 417 control group patients received American Heart Association phase II diet instruction, and the 421 intervention group patients received identical dietary instruction and underwent a partial ileal bypass operation. METHODS Four outcome measures were determined: 1) overall mortality, 2) coronary heart disease mortality, 3) coronary heart disease mortality and confirmed nonfatal myocardial infarction, and 4) coronary/cardiac interventions. RESULTS An overall mortality rate of 10% occurred at 6.7 years in the control group and 9.4 years in the intervention group, for a gain in disease-free interval of 2.7 years in the intervention group (p = 0.032). A coronary heart disease mortality rate of 8% occurred at 7.2 years in the control group and 11 years in the intervention group, for a gain of 3.8 years (p = 0.046). Twenty percent of patients demonstrated the combined end point of coronary heart disease mortality and confirmed nonfatal myocardial infarction at 5.9 years in the control group and 11.4 years in the intervention group, for a gain of 5.5 years (p < 0.001). Twenty-five percent of patients underwent either coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty or heart transplantation at 5.4 years in the control group and 12.4 years in the intervention group, for a gain of 7 years (p < 0.001). CONCLUSIONS The marked lipid modification achieved by partial ileal bypass in the POSCH trial led to demonstrable increases in the disease-free intervals for overall mortality, coronary heart disease mortality, coronary heart disease mortality and confirmed nonfatal myocardial infarction, and coronary intervention procedures. For the clinician and the patient, estimation of disease-free intervals may be more relevant than assessment of differences in incidence rates and risk ratios.

Impact of cholesterol reduction on peripheral arterial disease in the Program on the Surgical Control of the Hyperlipidemias (POSCH).

BACKGROUND Few lipid/atherosclerosis intervention trials have assessed the impact of cholesterol reduction on peripheral arterial disease. The 838 patients evaluated in the Program on the Surgical Control of the Hyperlipidemias (POSCH) trial represent more than the total number of patients in the seven previously reported studies. METHODS Peripheral arterial disease in POSCH was assessed by progression of clinical disease, serial changes in the systolic blood pressure ankle/brachial index (ABI), and changes on sequential peripheral arteriograms. RESULTS At the time of formal closure of the POSCH trial on July 19, 1990, claudication or limb-threatening ischemia was exhibited in 72 of 417 control group (CG) patients and in 54 of 421 intervention group (IG) patients (IG relative risk [RR] 0.702, 95% confidence interval [CI] 0.169 to 1.000, p = 0.049). With additional follow-up evaluation to September 30, 1994, clinical peripheral arterial disease was evident in 91 CG patients and 64 IG patients (RR 0.656, 95% CI 0.200 to 0.903, p = 0.009). At the 5-year follow-up evaluation, an ABI of less than 0.95 was present in 41 of 120 CG patients and in 24 of 126 IG patients, all of whom had an ABI of 0.95 or greater at baseline (RR in the IG of 0.557, 95% CI 0.360 to 0.863, p < 0.01). No appreciable differences were noted in the progression or regression of arteriographic peripheral arterial disease between the two groups. CONCLUSIONS Effective cholesterol reduction in POSCH led to statistically significant differences between the control and the intervention groups in the development of clinically evident peripheral arterial disease and in the ABI values, but not in the peripheral arteriograms. Additional studies need to assess the correlation between peripheral arterial changes and coronary arterial changes and clinical atherosclerosis events. Intervention trials that study peripheral arterial disease have intrinsic value in the evaluation of the impact of risk factor modification on progression of atherosclerotic peripheral arterial disease.

Studies on the neutropenia of cancer chemotherapy

Cancer patients who are receiving chemotherapy are considered to be at an increased risk of infection when the peripheral neutrophil count falls below 2000 cells/mm3. To protect them from such risk, the treatment is discontinued. The size of the marginal neutrophil pool, the extent of marrow neutrophil reserves, the patients ability to develop a tissue neutrophil and mononuclear cell response to a non‐specific inflammatory stimulus, and the in vitro metabolic activity of neutrophils were measured in 25 patients with solid tumors betore and after a course of chemotherapy. Results indicate that infection only occurred with a depression of marrow neutrophil reserves and/or a depression in the tissue neutrophil and mononuclear cell response to non‐specific inflammation. The functional capability of neutrophils, as measured by the in vitro metabolic responses to phagocytosis of latex particles, remained intact despite peripheral neutropenia. Chemotherapy may be safely continued, despite peripheral neutropenia, as long as the marrow reserves and tissue leukocyte inflammatory responses remain intact.

Overall mortality in the program on the surgical control of the hyperlipidemias.

BACKGROUND The Program on the Surgical Control of the Hyperlipidemias (POSCH), a secondary intervention trial, was the only lipid/atherosclerosis randomized clinical trial that used a surgical modality--partial ileal bypass. POSCH provided solid evidence for the clinical and arteriographic benefits of lipid profile normalization. Few longterm followup reports have been published in this field. This report concerns overall mortality, the primary endpoint of POSCH, with a mean followup of 18 years (range 15.5 to 23.0 years). STUDY DESIGN Overall mortality data were compiled from reports to the POSCH clinics, followup telephone calls, death certificates, and the US National Death Index. RESULTS There were 144 deaths in the control group (n = 417) and 120 deaths in the intervention group (n = 421), using intent-to-treat analysis. The risk reduction in the intervention group was 0.201 (20%); the risk ratio was 0.799, or 0.8 (95% confidence intervals, 0.628 to 1.018, p = 0.07). The proportion of patients alive was 65.7% in the control group and 72.0% in the intervention group, for a difference of 6.3% in the intervention group (p = 0.05). Kaplan-Meier survival analysis (p = 0.046) and disease-free intervals analysis at 70% survival (p < 0.001) were confirmatory. The gain in life expectancy in the intervention group was 2.7 years. CONCLUSIONS Longterm followup POSCH data demonstrate that lipid profile normalization will decrease overall mortality and will maintain a persistent and constant increase in life expectancy.

Plasma lipids and cardiovascular risk: a POSCH report

Quantifying the relationship between changes in lipid variables and clinical endpoints has been difficult. We studied the predictive value of various lipid variables on three endpoints in the Program on the Surgical Control of the Hyperlipidemias (POSCH): overall mortality, coronary heart disease (CHD) mortality, and CHD mortality and confirmed nonfatal myocardial infarction (MI) combined. We measured lipid variables for the annual visits from baseline to 5 years for actual follow-up values, actual and percentage differences between baseline and follow-up values, as well as the parameters comparing baseline only to 5 years for actual differences, percentage differences, and the ratio of baseline to 5 years. The lipid variables included were total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, triglycerides, and the LDL cholesterol/HDL cholesterol ratio. The analytic method used was that of Cox regression, with age and sex as secondary covariates, and each lipid or ratio of lipids as the primary (univariate) covariate. As a result, 108 univariate Cox regressions were conducted. The combined findings for the control and the intervention groups are presented. The number of events for the combined group were: overall mortality, 190; CHD mortality, 119; and CHD mortality and confirmed nonfatal MI, 262. The highest hazard ratios were found for the lipid variable of the LDL cholesterol/HDL cholesterol ratio (e.g. 1.196 for a 1-unit increase). Only for the combined endpoint of CHD mortality and confirmed nonfatal MI was there a substantial number of statistically significant relationships (P<0.01) of lipid variables and parameters of assessment.

Health and Numbers: Basic Biostatistical Methods

Proportions, Rates and Ratios Summarization of Continuous Measurements Probability and Probability Models Confidence Estimation Introduction to Hypothesis Testing Some Simple Statistical Methods Introduction to Other Selected Topics.

Discectomy Strategies for Lumbar Disc Herniation: Study Design and Implications for Clinical Research

Although previous studies have found automated percutaneous discectomy and epidural percutaneous discectomy to be less efficacious than conventional discectomy, these percutaneous procedures may be effective and cost-effective as a first surgical treatment for herniated lumbar disc. Percutaneous procedures for herniated lumbar disc continue to be performed throughout the world without definitive evidence of efficacy or effectiveness. The objective of this article is to report the design considerations and final design of a study with the following objectives: (1) to estimate the efficacy of automated percutaneous and conventional discectomy in treating single level herniated lumbar discs in comparable patient populations, and (2) to test the hypothesis that the use of percutaneous discectomy as the first surgical procedure in such patients would result in less cost and fewer complications than utilizing conventional discectomy as the first procedure. A multicenter randomized clinical trial was designed that followed published eligibility criteria closely, allowed flexibility in timing of surgery (while collecting natural history information on patients identified before electing surgery), incorporated adjustments for newly developed technology and accommodated the unusual demands of assessing a procedure acknowledged to have inferior medical outcomes when compared to conventional therapy but which offered potential advantages in cost and safety. The study was successfully designed and funded. In its implementation we experienced several obstacles that may affect the success of other clinical trials. Despite using established eligibility criteria, our patient enrollment was lower than expected. Academic health centers and traditional research settings are seeing fewer patients who would be eligible for discectomy; private clinical centers are treating eligible patients but lack the incentives to participate in clinical research. Automated percutaneous discectomy and epidural percutaneous discectomy are widely performed procedures and, despite the aforementioned obstacles, their efficacy and cost-effectiveness need to be scientifically evaluated if we are committed to delivering appropriate patient care.

Gender-based mortality follow-up from the Program on the Surgical Control of the Hyperlipidemias (POSCH) and meta-analysis of lipid intervention trials. Women in POSCH and other lipid trials.

OBJECTIVE The authors assessed the clinical results of lipid-lowering therapy in women. SUMMARY BACKGROUND DATA The Program on the Surgical Control of the Hyperlipidemias (POSCH) has demonstrated that effective lowering of total cholesterol and low-density lipoprotein cholesterol in a postmyocardial infarction population significantly reduces atherosclerotic coronary heart disease (ACHD) mortality, ACHD mortality combined with a new confirmed nonfatal myocardial infarction, and the number of coronary artery bypass grafting and angioplasty procedures performed. METHODS A review and meta-analysis were performed of the seven primary or secondary lipid/ atherosclerosis intervention trials-including POSCH-published in the English-language literature that included women and published results in women separate from the results in men or in the entire trial population. The main outcome measure analyzed was overall mortality. RESULTS The Scottish Physicians Clofibrate Study, the Newcastle upon Tyne Clofibrate Study, and the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I) Trial may have demonstrated a possible benefit in ACHD prognosis from effective lipid intervention in women. The other four available trials did not. The Minnesota Coronary Survey reported a 15.6% increase in overall mortality rate and a 30.6% increase in a combined cardiovascular endpoint rate in the lipid-intervention group. The Upjohn Colestipol Study demonstrated statistically significant reductions in overall and ACHD mortality in the men, but not in the women. The Scandinavian.

The effect of definitive irradiation on local control and disease free survival in breast cancer

The prognostic factors important in determining local regional control or failures can be divided into two groups. The first, the intrinsic factors, relate to the initial inherent condition of the tumor, that is, the tumor labeling index, progesterone receptors, the degree of involvement of the lymph nodes in he area, the size of the tumor, etc. The second, extrinsic factors, relate to type and adequacy of treatment. The presentation demonstrates that the most critical factors in determining failure and patterns of failure are the intrinsic factors, that is, histologic grade tumor labeling index, number of nodes involved, progesterone receptors and size, and that the adequacy of treatment affects failure and patterns of failure in patients treated. This paper shows that adequate radiation reduces local recurrence and, consequently, increases the survival rate; it also demonstrates that inadequate radiation will lead to increased local recurrence and decreased survival. The factors involved in determining the adequacy of irradiation are discussed.