Production of large amounts of hydrogen peroxide by human tumor cells.

Few nonphagocytic cells are known to generate reactive oxygen intermediates. Based on horseradish peroxidase-dependent, catalase-inhibitable oxidation of fluorescent scopoletin, seven human tumor cell lines constitutively elaborated H2O2 at rates (up to 0.5 nmol/10(4) cells/h) large enough that cumulative amounts at 4 h were comparable to the amount of H2O2 produced by phorbol ester-triggered neutrophils. Superoxide dismutase-inhibitable ferricytochrome c reduction was detectable at much lower rates. H2O2 production was inhibited by diphenyleneiodonium, a flavoprotein binder (concentration producing 50% inhibition, 0.3 microM), and diethyldithiocarbamate, a divalent cation chelator (concentration producing 50% inhibition, 3 microM), but not by cyanide or azide, inhibitors of electron transport, or by agents that inhibit xanthine oxidase, polyamine oxidase, or cytochrome P450. Cytochrome b559, present in human phagocytes and lymphocytes, was undetectable in these tumor cells by a sensitive spectrophotometric method. Mouse fibroblasts transfected with human tyrosinase complementary DNA made melanin, but not H2O2. Constitutive generation of large amounts of reactive oxygen intermediates, if it occurs in vivo, might contribute to the ability of some tumors to mutate, inhibit antiproteases, injure local tissues, and therefore promote tumor heterogeneity, invasion, and metastasis.

Risk factors for severe neuropsychiatric toxicity in patients receiving interferon alfa-2b and low-dose cytarabine for chronic myelogenous leukemia: analysis of Cancer and Leukemia Group B 9013.

PURPOSE: Recombinant interferon alfa-2b (rIFNalpha2b) is a standard therapy for chronic myelogenous leukemia (CML). Severe neuropsychiatric toxicity has been described in patients receiving rIFNalpha2b, although the frequency of and the risk factors for developing this toxicity are not well described. The purpose of this study was to identify predictors for the development of severe neuropsychiatric toxicity in CML patients receiving rIFNalpha2b-based therapy. PATIENTS AND METHODS: From a prospective cohort of 91 Philadelphia chromosome-positive, previously untreated, chronic-phase CML patients treated on Cancer and Leukemia Group B (CALGB) 9013, a phase II trial of rIFNalpha2b plus cytarabine, the following were recorded at baseline: age, sex, race, pretreatment history of neurologic or psychiatric diagnosis, spleen size, blood counts, and peripheral blast count. Best response to treatment, rIFNalpha2b cumulative dose, dose duration, and dose-intensity were recorded during follow-up. Severe neuropsychiatric toxicity was defined as grade 3 or 4 events, according to CALGB expanded common toxicity criteria. Univariate and multivariate logistic regression analyses were used to identify variables that were associated with the development of severe neuropsychiatric toxicity. RESULTS: Severe neuropsychiatric toxicity developed in 22 patients (24.0%; 95% confidence interval [CI], 15.2% to 32.8%). Toxicity resolved after withdrawal of treatment in all patients. Five of six patients developed recurrence of symptoms with rechallenge. Twelve (63%) of 19 patients with a pretreatment neurologic or psychiatric diagnosis developed severe neuropsychiatric toxicity, as compared with 10 (14%) of 72 patients without a pretreatment neurologic or psychiatric diagnosis (P =.001), resulting in a relative risk of 4. 55 (95% CI, 2.33 to 8.88) for developing severe neuropsychiatric toxicity. No other variables were independently associated with the development of neuropsychiatric toxicity. CONCLUSION: CML patients with a pretreatment history of a neurologic or psychiatric diagnosis are at significantly increased risk of developing severe neuropsychiatric toxicity during therapy with rIFNalpha2b plus cytarabine. Monitoring for neuropsychiatric symptoms and avoiding rechallenge are recommended measures for such patients receiving rIFNalpha2b-based therapy.

Parallel phase I studies of daunorubicin given with cytarabine and etoposide with or without the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age or older with acute myeloid leukemia: results of cancer and leukemia group B study 9420.

PURPOSE: The Cancer and Leukemia Group B conducted parallel phase I trials of cytarabine, daunorubicin, and etoposide (ADE) with or without PSC-833 (P), a modulator of p-glycoprotein-mediated multidrug resistance. PATIENTS AND METHODS: One hundred ten newly diagnosed patients > or = 60 years of age with de novo acute myeloid leukemia (AML) were treated. All patients received cytarabine by continuous infusion for 7 days at 100 mg/m(2)/d. The starting dose of daunorubicin was 30 mg/m(2)/d for 3 days. Etoposide was administered at a dose of 100 mg/m(2)/d for 3 days, except in the last cohort administered ADEP, who received 60 mg/m(2). PSC-833 was given intravenously with a loading dose of 1.5 mg/kg over 2 hours and a simultaneous continuous infusion of 10 mg/kg/d continued until 24 hours after the last dose of daunorubicin or etoposide. RESULTS: There was no toxicity attributed to the PSC-833. Dose-limiting toxicity was primarily gastrointestinal (diarrhea, mucositis in the ADEP group). The estimated maximum-tolerated doses, calculated using a logistic regression model, were daunorubicin 40 mg/m(2)/d for 3 days with etoposide 60 mg/m(2) for 3 days in the ADEP group and daunorubicin 60 mg/m(2)/d for 3 days and etoposide 100 mg/m(2)/d for 3 days in the ADE group. Twenty-one (48%) of 44 patients achieved complete remission with ADE, compared with 29 (44%) of 66 patients treated with ADEP. CONCLUSION: It is necessary to decrease the doses of daunorubicin and etoposide when they are administered with PSC-833, presumably because of the effect of the modulator on the pharmacokinetics of these agents. A phase III trial comparing the regimens derived from this phase I trial has recently begun.

Phase III study of cyclophosphamide, doxorubicin, and fluorouracil (CAF) plus leucovorin versus CAF for metastatic breast cancer: Cancer and Leukemia Group B 9140.

PURPOSE: To determine whether biochemical modulation with LV (leucovorin) enhances the efficacy of CAF (cyclophosphamide, doxorubicin, and fluorouracil) against metastatic breast cancer. PATIENTS AND METHODS: Women with histologically confirmed stage IV breast cancer, Cancer and Leukemia Group B (CALGB) performance status 0 to 2, and no prior chemotherapy for metastatic disease were randomly assigned to receive CAF (cyclophosphamide 500 mg/m2 day 1, doxorubicin 40 mg/m2 day 1, and fluorouracil [FU] 200 mg/m2 intravenous bolus days 1 to 5) with or without LV (LV 200 mg/m2 over 30 minutes days 1 to 5 given 1 hour before FU). RESULTS: Two hundred forty-two patients were randomly assigned to treatment; 124 patients had visceral crisis and 40 patients had a CALGB performance status score of 2. The median follow-up was 6 years. The two study arms were similar with regard to serious adverse events; four patients died from treatment-related causes, two patients on each study arm. Predictive variables for time to treatment failure and survival were visceral disease and performance status. The overall response rate was 29% for CAF versus 28% for CAF plus LV. The median time to treatment failure (9 months) and median survival (1.7 years) did not differ by treatment arm. CONCLUSION: Modulation of CAF with LV improved neither response rates nor survival among women with metastatic breast cancer, compared with CAF alone. Multivariate analyses confirmed the prognostic importance of performance status and visceral crisis. However, the overall and complete response rates, response durations, time to treatment failure, and survival were the same in the two treatment arms.

Value of molecular monitoring during the treatment of chronic myeloid leukemia: a Cancer and Leukemia Group B study.

PURPOSE: Disappearance of the Philadelphia chromosome during treatment for chronic myeloid leukemia (CML) has become an important therapeutic end point. To determine the additional value of molecular monitoring during treatment for CML, we performed a prospective, sequential analysis using quantitative Southern blot monitoring of BCR gene rearrangements of blood and marrow samples from Cancer and Leukemia Group B (CALGB) study 8761. PATIENTS AND METHODS: Sixty-four previously untreated adults with chronic-phase CML who were enrolled onto CALGB 8761, a molecular-monitoring companion study to a treatment study for adults with chronic-phase CML (CALGB 9013). Treatment consisted of repetitive cycles of interferon alfa and low-dose subcutaneous cytarabine. Blood and marrow Southern blot quantitation of BCR gene rearrangements was compared with marrow cytogenetic analysis before the initiation of treatment and of specified points during therapy. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis was performed to detect residual disease in patients who achieved a complete response by Southern blot or cytogenetic analysis. RESULTS: Quantitative molecular monitoring by Southern blot analysis of blood samples was found to be equivalent to marrow monitoring at all time points. Twelve of 62 (19%) follow-up samples studied by Southern blot analysis had a complete loss of BCR gene rearrangement in matched marrow and blood specimens. Southern blot monitoring of blood samples was also found to be highly correlated to marrow cytogenetic evaluation at all points, although there were four discordant cases in which Southern blot analysis of blood showed no BCR gene rearrangement, yet demonstrated from 12% to 20% Philadelphia chromosome-positive metaphase cells in the marrow. RT-PCR analysis detected residual disease in five of six patients in whom no malignant cells were detected using Southern blot or cytogenetic analyses. CONCLUSION: Quantitative Southern blot analysis of blood samples may be substituted for bone marrow to monitor the response to therapy in CML and results in the need for fewer bone marrow examinations. To avoid overestimating the degree of response, marrow cytogenetic analysis should be performed when patients achieve a complete response by Southern blot monitoring. This approach provides a rational, cost-effective strategy to monitor the effect of treatment of individual patients, as well as to analyze large clinical trials in CML.

American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants.

PURPOSE: Because toxicities associated with chemotherapy and radiotherapy can adversely affect short- and long-term patient quality of life, can limit the dose and duration of treatment, and may be life-threatening, specific agents designed to ameliorate or eliminate certain chemotherapy and radiotherapy toxicities have been developed. Variability in interpretation of the available data pertaining to the efficacy of the three United States Food and Drug Administration-approved agents that have potential chemotherapy- and radiotherapy-protectant activity-dexrazoxane, mesna, and amifostine-and questions about the role of these protectant agents in cancer care led to concern about the appropriate use of these agents. The American Society of Clinical Oncology sought to establish evidence-based, clinical practice guidelines for the use of dexrazoxane, mesna, and amifostine in patients who are not enrolled on clinical treatment trials. METHODS: A multidisciplinary Expert Panel reviewed the clinical data regarding the activity of dexrazoxane, mesna, and amifostine. A computerized literature search was performed using MEDLINE. In addition to reports collected by individual Panel members, all articles published in the English-speaking literature from June 1997 through December 1998 were collected for review by the Panel chairpersons, and appropriate articles were distributed to the entire Panel for review. Guidelines for use, levels of evidence, and grades of recommendation were reviewed and approved by the Panel. Outcomes considered in evaluating the benefit of a chemotherapy- or radiotherapy-protectant agent included amelioration of short- and long-term chemotherapy- or radiotherapy-related toxicities, risk of tumor protection by the agent, toxicity of the protectant agent itself, quality of life, and economic impact. To the extent that these data were available, the Panel placed the greatest value on lesser toxicity that did not carry a concomitant risk of tumor protection. RESULTS AND CONCLUSION: Mesna: (1) Mesna, dosed as detailed in these guidelines, is recommended to decrease the incidence of standard-dose ifosfamide-associated urothelial toxicity. (2) There is insufficient evidence on which to base a guideline for the use of mesna to prevent urothelial toxicity with ifosfamide doses that exceed 2.5 g/m(2)/d. (3) Either mesna or forced saline diuresis is recommended to decrease the incidence of urothelial toxicity associated with high-dose cyclophosphamide use in the stem-cell transplantation setting. Dexrazoxane: (1) The use of dexrazoxane is not routinely recommended for patients with metastatic breast cancer who receive initial doxorubicin-based chemotherapy. (2) The use of dexrazoxane may be considered for patients with metastatic breast cancer who have received a cumulative dosage of 300 mg/m(2) or greater of doxorubicin in the metastatic setting and who may benefit from continued doxorubicin-containing therapy. (3) The use of dexrazoxane in the adjuvant setting is not recommended outside of a clinical trial. (4) The use of dexrazoxane can be considered in adult patients who have received more than 300 mg/m(2) of doxorubicin-based therapy for tumors other than breast cancer, although caution should be used in settings in which doxorubicin-based therapy has been shown to improve survival because of concerns of tumor protection by dexrazoxane. (5) There is insufficient evidence to make a guideline for the use of dexrazoxane in the treatment of pediatric malignancies, with epirubicin-based regimens, or with high-dose anthracycline-containing regimens. Similarly, there is insufficient evidence on which to base a guideline for the use of dexrazoxane in patients with cardiac risk factors or underlying cardiac disease. (6) Patients receiving dexrazoxane should continue to be monitored for cardiac toxicity. Amifostine: (1) Amifostine may be considered for the reduction of nephrotoxicity in patients receiving cisplatin-based chemoth

Progenitor cell transplantation for chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML), a myeloproliferative disorder characterized by the clonal proliferation of a hematopoietic stem cell, is a malignancy for which allogeneic bone marrow transplantation (BMT), when available, constitutes a mainstay of treatment. Several clinical considerations, especially the patient's age, influence the availability and likely outcome of BMT for patients with CML. Recent advances in nontransplant treatments for CML, notably interferon-alpha, have made the decision about the implementation and timing of BMT in CML more complex. Areas of active investigation include transplantation from a matched unrelated donor (MUD) and autologous BMT.

Validation of a combined comorbidity index.

The basic objective of this paper is to evaluate an age-comorbidity index in a cohort of patients who were originally enrolled in a prospective study to identify risk factors for peri-operative complications. Two-hundred and twenty-six patients were enrolled in the study. The participants were patients with hypertension or diabetes who underwent elective surgery between 1982 and 1985 and who survived to discharge. Two-hundred and eighteen patients survived until discharge. These patients were followed for at least five years post-operatively. The estimated relative risk of death for each comorbidity rank was 1.4 and for each decade of age was 1.4. When age and comorbidity were modelled as a combined age-comorbidity score, the estimated relative risk for each combined age-comorbidity unit was 1.45. Thus, the estimated relative risk of death from an increase of one in the comorbidity score proved approximately equal to that from an additional decade of age. The combined age-comorbidity score may be useful in some longitudinal studies to estimate relative risk of death from prognostic clinical covariates.

Long-term prognosis after peri-operative cardiac complications.

UNLABELLED: The objective was to document the 5 year prognosis of patients who had cardiac complications after non-cardiac surgery. DESIGN: 5-year follow-up of 218 patients originally enrolled in a prospective study to identify risks factors for peri-operative complications. SETTING: an academic medical center. Participants were hypertensives and diabetics who underwent elective surgery between 1982 and 1985. In the original study, patients were evaluated pre-operatively, monitored intra-operatively by an independent observer, and followed daily for 7 days post-operatively according to a standard surveillance protocol. Outcomes were judged by assessors blinded to the pre-operative status and intra-operative course. Patients were interviewed at 3 and 5 years post-operatively. Patients with post-operative cardiac complications had significantly higher rates of overall mortality, mortality attributable to cardiac causes (MI, CHF, arrest), and mortality attributable to other cardiovascular causes (stroke, renal failure) than patients without cardiac complications. For example, at 5 years 11% of those patients without post-operative cardiac complications had cardiac deaths, in contrast to 45% of those patients with post-operative cardiac complications. Proportional hazards analysis demonstrated that post-operative cardiac complications remained a significant predictor of cardiac (p < 0.001) and cardiovascular (p < 0.0001) mortality controlling for pre-operative cardiac disease, other non-cardiovascular comorbid diseases, age, sex, diabetes, and pre-operative renal insufficiency or stroke. Similarly, patients with post-operative non-fatal cardiac complications had higher rates of cardiac or cardiovascular events during the 5 year follow-up period. We conclude that post-operative cardiac complications have a significant adverse long-term prognostic impact comparable to the prognostic impact of myocardial infarction, ischemia or congestive failure in the non-operative setting. Understanding these events could be an important factor in identifying patients at high risk for subsequent peri-operative complications.

Improvement of outcomes after coronary artery bypass. A randomized trial comparing intraoperative high versus low mean arterial pressure.

BACKGROUND: The objective of this randomized clinical trial of elective coronary artery bypass grafting was to investigate whether intraoperative mean arterial pressure below autoregulatory limits of the coronary and cerebral circulations was a principal determinant of postoperative complications. The trial compared the impact of two strategies of hemodynamic management during cardiopulmonary bypass on outcome. Patients were randomized to a low mean arterial pressure of 50 to 60 mm Hg or a high mean arterial pressure of 80 to 100 mm Hg during cardiopulmonary bypass. METHODS: A total of 248 patients undergoing primary, nonemergency coronary bypass were randomized to either low (n = 124) or high (n = 124) mean arterial pressure during cardiopulmonary bypass. The impact of the mean arterial pressure strategies on the following outcomes was assessed: mortality, cardiac morbidity, neurologic morbidity, cognitive deterioration, and changes in quality of life. All patients were observed prospectively to 6 months after the operation. RESULTS: The overall incidence of combined cardiac and neurologic complications was significantly lower in the high pressure group at 4.8% than in the low pressure group at 12.9% (p = 0.026). For each of the individual outcomes, the trend favored the high pressure group. At 6 months after coronary bypass for the high and low pressure groups, respectively, total mortality rate was 1.6% versus 4.0%, stroke rate 2.4% versus 7.2%, and cardiac complication rate 2.4% versus 4.8%. Cognitive and functional status outcomes did not differ between the groups. CONCLUSION: Higher mean arterial pressures during cardiopulmonary bypass can be achieved in a technically safe manner and effectively improve outcomes after coronary bypass.

Clinical reproducibility of dual energy x-ray absorptiometry.

Dual energy x-ray absorptiometry is a technique advocated for the measurement of bone mass throughout the skeleton, and recently it has been used to measure changes in periprosthetic bone mass after joint replacement. The accuracy and precision of the method in clinical patient populations have not been firmly established. This study sought to establish the short-term reproducibility of measurements made with dual energy x-ray absorptiometry of multiple sites in a large sample of elderly patients with rheumatic disease. Reproducibility was assessed in the lumbar spine and in three femoral sites in 69 patients participating in a longitudinal clinical trial. In each patient, absorptiometry was performed twice in the same day at as many as five time points over a 2-year period. The mean (+/- SD) baseline bone density was 0.783 +/- 0.128 g/cm2 for the femoral neck and 1.015 +/- 0.218 g/cm2 for the lumbar spine. The correlations between the duplicate baseline measurements of the spine were excellent (r = 0.9936, p < 0.001) and were stable over the 2-year period; the mean difference between the duplicate baseline measurements was 1.82 +/- 1.54% and the mean coefficient of variation was 1.29%. Measurements in the femur were much less precise; these values were 3.61 +/- 3.14% and 2.55% in the femoral neck, 3.66 +/- 4.35% and 2.59% in the greater trochanter, and 5.28 +/- 5.61% and 3.73% in Ward's triangle. This study evaluated the short-term reproducibility of dual energy x-ray absorptiometry in a clinical population.(ABSTRACT TRUNCATED AT 250 WORDS)

A self-administered hip-rating questionnaire for the assessment of outcome after total hip replacement.

The hip-rating questionnaire was developed for the assessment of the outcome of total hip replacement. The purpose of this study was to evaluate its reproducibility, validity, and responsiveness. The questionnaire uses a 100-point scale in which equal weight is given to the domains of global or over-all impact of arthritis, pain, walking, and function. Ninety-eight patients were enrolled in the prospective study and have been followed for at least three months; sixty-two patients have been followed for six months; and forty-two patients have been followed for one year. Reproducibility was tested with the use of the kappa statistic in fifty patients whose condition was stable clinically, and it was found to be good or excellent both for individual questions and for the total score. The validity of the questionnaire was assessed by comparison with the scores from a six-minute walking-distance test and arthritis impact-measurement scales. The result of the six-minute walking-distance test correlated with the patient's response concerning walking distance on the hip-rating questionnaire. The score for pain from the hip-rating questionnaire correlated well with the score for pain from the arthritis impact-measurement scales, and the total score from the hip-rating questionnaire correlated well with the total score from the arthritis impact-measurement scales. The score on the hip-rating questionnaire was responsive to the change in the clinical condition of the patient, as indicated by a favorable index of responsiveness. The results of the questionnaire were sensitive enough to demonstrate differences among treatment groups with relatively small sample sizes. This questionnaire has the characteristics of a useful instrument for assessment of outcomes, such as that after an operation.

Geographic variations in the rates of elective total hip and knee arthroplasties among Medicare beneficiaries in the United States.

We analyzed the variations in the rates of elective total hip and total knee arthroplasties for 1988 in the United States to determine whether the rates correlated with the numbers of surgeons. There were 56,204 total hip arthroplasties and 68,491 total knee arthroplasties, performed in the home states of the patients among all of the Medicare beneficiaries. Medicare beneficiaries include most people who are more than sixty-five years old in the United States and a small proportion of younger people who are eligible for Medicare for other reasons. Seventy-nine per cent of the patients who had had a total hip arthroplasty and 89 per cent of those who had had a total knee arthroplasty had been managed with the operation because of osteoarthrosis. Both operations were most common in the seventy to seventy-four-year age-group. We calculated the rate of operations per 100 beneficiaries for each state and age-adjusted the results. Across all of the states, bilateral procedures constituted 1.6 per cent of the total hip arthroplasties and 4.8 per cent of the total knee arthroplasties. The in-hospital rates of mortality were 0.72 per cent for total hip arthroplasties and 0.45 per cent for total knee arthroplasties. The destinations after discharge from the hospital were similar for the two groups of patients, with more than 65 per cent of the patients being discharged directly to their homes. There were no significant differences among states in terms of the length of stay in the hospital or reimbursement of the hospital.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase II trial of topotecan in advanced breast cancer: a Cancer and Leukemia Group B study.

The topoisomerase I inhibitor topotecan had demonstrated good antitumor activity in several murine tumor systems and in human clonogenic assays by 1993. In that year, the Cancer and Leukemia Group B (CALGB) began a phase II trial to determine its activity in patients with breast cancer who had previously received one course of chemotherapy for advanced breast cancer. Between April 1993 and June 1994, 53 patients of performance status 0-2 entered the study, of whom 47 were eligible and 40 were evaluable. Topotecan was given at a dose of 1.5 mg/m2 over 30 minutes daily for 5 days every 21 days. In the absence of progression or withdrawal of consent, therapy was continued indefinitely. The median age was 58 years (range 30-79). There were no complete responses and four partial responses, resulting in an objective response rate of 10% (95% CI: 3-24%). Responses were noted in lymph nodes, liver, and skin. The median duration of response was 5 months. The median survival was 12 months. Life-threatening toxicities were almost exclusively hematologic. However, myelosuppression was not cumulative. It was concluded that topotecan has only modest activity among women with advanced breast cancer who have previously received one course of chemotherapy. Given its modest activity and predominant hematologic toxicity, it does not appear to be a promising drug for either single-agent or combination chemotherapy in the salvage setting of advanced breast cancer.

Uses of intravenous gammaglobulin in immune hematologic disease.

In summary, for intravenous gammaglobulin use of ITP in children and adults, it is clear that intravenous gammaglobulin is an effective way to increase the platelet count acutely and this will be faster than or as fast as any other therapy. However, there is no proven curative effect of IV gammaglobulin. Its use in situations requiring a rapid increase in the platelet count seems secure as does its use in children with chronic ITP. The latter however and the treatment of HIV-ITP may find IVIG treatment largely replaced in the future by IV Anti-D(10) which is currently experimental. The use of a viral inactivated form of IVIG currently seems mandatory to avoid post-transmission hepatitis.

Cognitive effects after epidural vs general anesthesia in older adults. A randomized trial.

OBJECTIVE: To compare the effect of epidural vs general anesthesia on the incidence of long-term cognitive dysfunction after total knee replacement surgery in older adults. DESIGN: Randomized controlled clinical trial. SETTING: Orthopedic specialty academic hospital. PATIENTS: A total of 262 patients undergoing elective primary total knee replacement with a median age of 69 years; 70% women. INTERVENTION: Random assignment to either epidural or general anesthesia. MAIN OUTCOME MEASURES: A thorough neuropsychological assessment was performed preoperatively and repeated at 1 week and 6 months postoperatively. Cognitive outcome was assessed by within-patient change on 10 tests of memory, psychomotor, and language skills. Prospective standardized surveillance for cardiovascular complications was performed to allow simultaneous assessment of anesthetic effects on cognitive and cardiovascular outcomes. RESULTS: The two groups were similar at baseline in terms of age, sex, comorbidity, and cognitive function. There were no significant differences between the epidural and general anesthesia groups in within-subject change from baseline on any of the 10 cognitive test results at either 1 week or 6 months. Overall, 5% of patients showed a long-term clinically significant deterioration in cognitive function. There was no difference between the anesthesia groups in the incidence of major cardiovascular complications (3% overall). CONCLUSIONS: The type of anesthesia, general or epidural, does not affect the magnitude or pattern of postoperative cognitive dysfunction or the incidence of major cardiovascular complications in older adults undergoing elective total knee replacement. This is the largest trial of the effects of general vs regional anesthesia on cerebral function reported to date, with more than 99% power to detect a clinically significant difference on any of the neuropsychological tests.

Leukocyte counts and cerebrovascular disease.

Elevated total leukocyte count in a biennial examination period is shown to be a significant (p = 0.001) predictor of cerebral infarction (CI) incidence in the subsequent 2 yr examination period, in a large Japanese cohort study. This association is not explainable on the basis of corresponding age, sex or blood pressure levels. The extent to which the association might be attributable to cigarette smoking habits could not be thoroughly examined with available data. Relative risks associated with a specific elevated leukocyte count may be larger among persons less than 65 yr of age than among older persons. When counts of specific leukocyte cell lines are considered a significant (p = 0.0006) role for neutrophil count emerges, while an additional predictive role for other leukocyte cell types could not be detected. In contrast, there is a suggestion that cerebral hemorrhage (CH) risk may be lower following an elevated leukocyte count. In particular, a negative association between lymphocyte count and CH incidence in the subsequent biennial examination cycle, is nearly significant (p = 0.07), in spite of a rather small number of CH cases in the sample.

High reproducibility in the interpretation of intraoperative transesophageal echocardiographic evaluation of aortic atheromatous disease.

Intraoperative decisions are often based on interpretation of results from transesophageal echocardiography (TEE). One such area is the intraoperative evaluation of atheromatous disease of the thoracic aorta and subsequent classification or grading. These grading schemes are predictive of stroke after cardiac surgery. Since intraoperative strategies may be modified based on this TEE aortic atheroma grading, assessment of the interobserver variability of TEE findings between observers is essential. Forty TEE videotape segments imaging three portions of the thoracic aorta (ascending, arch, descending) were selected from 189 reports of a larger cohort. Three independent, blinded observers, experienced in TEE, evaluated these examinations for atheroma severity. If a TEE segment had insufficient data, "uninterpretable" was recorded. Weighted kappa coefficients of agreement were calculated on the three data sets. Mean weighted kappa coefficients for the three observers A, B, and C were 0.69, 0.74, and 0.72, for the ascending, arch, and descending aorta segments, respectively, representing excellent agreement. We have demonstrated uniformly high agreement for interpretation of TEE, which indicates the excellent reproducibility of TEE grading and stratification of aortic atheroma. Reproducibility within and across specialties and institutions is essential for widespread application of TEE for evaluation of the thoracic aorta.

Leukocyte counts and coronary heart disease in a Japanese cohort.

Coronary heart disease incidence during 1958-1974, in a cohort of Hiroshima and Nagasaki residents, was found to relate significantly (p = 0.01) to total leukocyte count, taken an average of two years earlier. Relative risks, as a function of leukocyte count, did not appear to depend on sex or cigarette smoking status, but may be larger for subjects less than 65 years of age than for older persons. This study examines, for the first time, differential leukocyte counts and percentages in relation to coronary heart disease incidence. Both neutrophil count and eosinophil count significantly relate to coronary heart disease incidence, while there is also a suggestion for a relationship with monocyte count. A possible immunopathologic basis for such associations is mentioned. It will be important for other studies to confirm these relationships, however, as the present data do not allow one to clearly show the relative risk, at a specified total leukocyte count, to depend on the differential leukocyte fractions. Available data also leave uncertainty concerning the "independence" of leukocyte counts in the specification of coronary heart disease risk, relative to such known risk factors as cigarette smoking habits and serum cholesterol levels.

Serum cholesterol, other risk factors, and cardiovascular disease in a Japanese cohort.

The relationship of serum cholesterol and other risk factors to cardiovascular disease was investigated in a 16-year cohort of 16,711 residents of Hiroshima and Nagasaki. Examined in detail were the relationship of serum cholesterol, and the joint relationships of serum cholesterol, systolic blood pressure, diastolic blood pressure, and other risk factors to coronary heart disease (CHD), cerebral infarction (CI), and cerebral hemorrhage (CH). Baseline and biennially collected risk factor data were analyzed. The latter type of measurement permitted separate investigation of both the short-term and long-term effects of cholesterol measurements. In both types of analyses, both serum cholesterol and blood pressure showed strong associations with CHD incidence. In particular, there were strong associations with short-term and delayed CHD incidence. Furthermore, the association of cholesterol with short-term CHD incidence could not be explained by its association with delayed CHD incidence, or vice versa. Multivariate analyses that also included several other risk factors (smoking habits, clinical diagnosis of diabetes mellitus, left ventricular hypertrophy or strain on electrocardiogram, relative body weight, hematocrit, and proteinuria) for which data were available showed such risk factors to be of lesser, but generally non-negligible, importance in this population. In the case of CH and CI, serum cholesterol was found to be weakly or not at all related to incidence of either disease while blood pressure remained a strong correlate. For CI some suggestion of a statistical interaction between blood pressure and serum cholesterol was found. Discussed are implications for theories of disease pathogenesis for CHD, CI and CH.