Anthracyclines and the heart

Cardiotoxicity is the most important side effect of the highly effective chemotherapeutic drugs anthracyclines. The total dose that must not be surpassed to avoid cardiotoxicity is specific for each anthracycline. For doxorubicin the maximal dose is 450-550 mg/mq. Nevertheless cardiotoxicity can be observed in some cases even with doses smaller than the critical ones. Clinical signs of cardiotoxic damage can appear at any stage during the course of therapy. The prevention of cardiac damage can be tried in three ways. Firstly one should extend the administration period of the total dose of the drug for about 6 hours. The second way is based on the use of anthracycline analogs less toxic and possibly equally effective than doxorubicin. Finally one can associate to the anthracycline a cardioprotective drug such as ICRF187. The diagnosis of cardiotoxicity is usually reached evaluating the reduction of left ventricular ejection fraction either with echocardiography or with angiocardiography. Other parameters, particularly those evaluating the diastolic function, are under study to make the diagnosis more quick and accurate. Both cardiac scintigraphy and tomography also seem to offer promising tools for the diagnosis of anthracycline cardiotoxicity. Endomyocardiac biopsy is highly effective for the diagnosis, but is indicated only for selected cases. The therapy of anthracycline cardiomyopathy is directed mainly to the control of congestive heart failure. In the initial phase the treatment is based on the use of digitalis and diuretics, that are substituted in the following maintaining phase by ACE inhibitors.     

Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer

PURPOSE: To evaluate the influence of cumulative dose, dose-intensity, single-dose level, and schedule of epirubicin on the risk of developing congestive heart failure (CHF) in patients with advanced breast cancer. PATIENTS AND METHODS: Four hundred sixty-nine consecutive anthracyline-naive patients with metastatic breast cancer were included. Only patients with cardiac failure according to New York Heart Association (NYHA) function class II or more were recorded as having CHF. For each patient, the following were calculated: the cumulative dose of epirubicin, mean dose-intensity (cumulative dose of epirubicin/duration of treatment), and single-dose level (cumulative dose of epirubicin/number of injections). RESULTS: Thirty-four patients (7.2%) developed CHF. The cumulative risk of cardiotoxicity was 4% at 900 mg/m2 and increased exponentially to 15% at 1,000 mg/m2. Irradiation against the mediastinum and thoracic spine increased the risk of CHF (P=.025), but dose-intensity, single-dose level, and schedule had no influence on the risk of developing CHF. Age, previous adjuvant irradiation (to the left or right hemithorax), and previous chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [CMF]) were not risk factors. The median time to onset of CHF following the last dose of epirubicin was 57 days (range, 0 to 853). Among patients with CHF, 13 (38.2%) died of cardiac failure. The median survival time for all patients with CHF was 162 days (range, 0 to +1,957). Previous irradiation directly against the heart increased the risk of death due to cardiac failure and decreased the median survival time to 125 days (range, 0 to 336). CONCLUSION: The present large retrospective study of 469 patients substantiates previous results concerning the cardiotoxicity of epirubicin. A significantly increasing risk of CHF in patients who receive cumulative doses greater than 950 mg/m2 was established. The future recommended maximum cumulative dose of epirubicin should be 900 mg/m2 in patients with metastatic breast cancer. Previous irradiation against the heart leads to an increased risk of developing CHF with an accelerated course to death, which indicates an additive cardiotoxic effect of irradiation and epirubicin.     

Quality assurance in renography: a review

BACKGROUND: Pegylated liposomal doxorubicin (PL-DOX) has been shown in preclinical models to induce less cardiotoxicity than non-liposomal doxorubicin. Endomyocardial biopsy is a highly sensitive and specific method for detecting anthracycline-induced cardiac damage. PATIENTS AND METHODS: Myocardial tissue from ten KS patients who had received cumulative PL-DOX (20 mg/m2/biweekly) of 440-840 mg/m2 was evaluated for evidence of anthracycline-induced cardiac damage. Controls were assembled from patients who had received cumulative doxorubicin doses of 174-671 mg/m2 in two earlier cardiac biopsy protocols. Two control groups were selected on the basis of both cumulative (+/- 10 mg/m2) and peak doxorubicin dose (60 or 20 mg/m2, control group 1), or peak dose alone (20 mg/m2, control group 2). RESULTS: PL-DOX patients had significantly lower biopsy scores compared with those of doxorubicin controls despite higher cumulative doses of anthracycline. The median biopsy scores for the PL-DOX and doxorubicin groups, respectively, were 0.3 vs. 3.0 (P = 0.002, Cochran-Mantel-Haenszel row mean difference test) for group 1 and 1.25 for group 2 (P < 0.001, Wilcoxon rank-sum test). CONCLUSIONS: Less severe cardiac changes were seen in patients given PL-DOX relative to historical control patients given comparable cumulative doses of doxorubicin.     

Cardiotoxicity of 5-fluorouracil in combination with folinic acid in patients with gastrointestinal cancer

BACKGROUND: Cardiotoxicity related to the widely used cytotoxic compound 5-fluorouracil (5-FU) is rare compared with the frequency observed with the use of anthracyclines. More effective protocols incorporating active biomodulatory compounds like folinic acid (FA) or combination chemotherapy change type and severity of toxicity as well. The objective of the current study was to assess cardiotoxicity of the combination 5-FU and folinic acid. METHODS: The authors' multicenter experience with 390 patients treated for advanced gastrointestinal cancer with intermediate-dose folinic acid and 5-FU was reviewed. RESULTS: The overall risk of cardiotoxicity was 3%, which is not significantly higher than that reported with 5-FU alone. Eight of 53 patients with a history of cardiac disease reported cardiac symptoms (15.1%), compared with 5 of 337 patients (1.5%) with a no history of cardiac disease. Median time to symptoms was 3 days (range, 2-6). Nine patients had symptoms resembling myocardial ischemia, one patient died due to assumed myocardial infarction related closely to fluorouracil treatment, four patients had supraventricular arrhythmia, and one patient had congestive heart failure. A history of cardiac disease was the only risk factor associated with cardiotoxicity. Relapses were frequent on reinstitution of therapy despite cardiac symptoms in the preceding cycle. Therapeutically or prophylactically administered nitrates had no significant effect. CONCLUSION: Physicians should be aware of the cardiotoxic properties of active fluorouracil treatment. The combination of 5-FU and leucovorin does not differ from single-agent therapy in frequency or type of cardiotoxicity. Close monitoring of patients is mandatory, especially for those patients at high risk for cardiac side effects. Treatment should be discontinued if coronary symptoms develop, because neither effective treatment nor prophylaxis exists for such symptoms.     

High-resolution electrocardiography in monitoring myocardial damage after therapy with anthracyclines in children

BACKGROUND: Anthracycline cytostatics, widely used in oncologic practice, may induce discrete myocardial damage occasionally culminating in life-threatening cardiologic complications. The most serious clinical manifestations of anthracycline cardiotoxicity are dilated cardiomyopathy, heart failure and fatal arrhythmias. OBJECTIVES, STARTING POINT AND MAIN PURPOSE: High-resolution electrocardiography (HRECG) is one of the latest cardiologic methods, which can be promising for early identification of patients at risk of anthracycline cardiotoxicity. The aim of this study is the evaluation of the incidence of HRECG abnormalities in a group of paediatric patients treated with anthracyclines and the usefulness of HRECG for stratification of patients at risk of the clinical cardiotoxicity. PATIENTS AND METHODS: A set of 60 oncologic paediatric patients treated with anthracyclines was divided into two groups. The first group was formed by 15 patients undergoing evaluation during their anthracycline therapy (median after the last administration of antracyclines was 3.2 days). Their average age at the time of examination was 14.7 +/- 4.1 years. The total cumulative dose of antracyclines was 40-300 mg/m2 (median 150 mg/m2). The second group was formed by 45 patients who were evaluated after completing anthracycline therapy. The interval of time from the last administration of antracycline in this subgroup of patients was 3 months-12 years (median 5.5 years). Their average age at the time of HRECG examination was 14 +/- 4.1 years. The total cumulative dose of anthracyclines was 90-440 mg/m2 (median 230 mg/m2). Six patients of this group (13.3%) were treated also with mediastinal radiotherapy (18-40 Gy). 43 patients (95.5%) of second group were in complete remission, two other patients yielded a progression of their malignancy. 10 patients (22%) were examined by HRECG 2-5 times in app. two-month intervals. The control group was formed by 30 randomly selected healthy children and adolescents with normal ECG. Average age was 15.1 +/- 5.8 years. Using HRECG the time- and frequency-domain characteristics of the ECG signal were analyzed. The time-domain analysis was performed at 40-250 Hz filter. The frequency-domain analysis was performed by fast Fourier transformation (FFT), a 120 ms segment starting 20 ms before the end of the QRS complex was analyzed. The altered frequency content was expressed as the ratio of frequency areas (area ratio, AR) 20-50 Hz/0-20Hz. The average level of noise was 0.56 microV in the first group, 0.62 microV in the second group of patients and 0.68 microV in the control group. RESULTS: Abnormalities in the time-domain analysis (ventricular late potentials, VLP) were present in 2 (13.3%) of 15 patients during the anthracycline therapy in the first group and in 4 (8.8%) of 45 patients after completing therapy in the second group. No abnormalities in the time-domain analysis were detected in the control group. Using frequency-domain analysis, abnormalities in AR20-50 Hz/0-20 Hz were found in 8 (53.3%) of 15 patients of the first group, and in 11 (24.4%) of 45 patients of the second group. Significant differences were observed in the frequency parameters of the ECG signal in patients of the first group in comparison to the control group (p = 0.0018) and also when comparing the patients of the second group and the control group (p = 0.045). CONCLUSION: The HRECG results in time- and frequency-domain analyses indicate to high incidence of HRECG abnormalities in patients examined both during and after the antracycline therapy in comparison to the control group. The prognostic use of the HRECG abnormalities must be established in a larger and longer study. (Fig. 4, Tab. 2, Ref. 43.)     

Gynaecological examination: a teaching package integrating assessment with learning (693)

Race and gender are important determinants of certain clinical outcomes in cardiovascular disease. To examine the influence of race and gender on care process, resource use, and hospital-based case outcomes for patients with congestive heart failure (CHF), we obtained administrative records on all 1995 New York State hospital discharges assigned ICD-9-CM codes indicative of this diagnosis. The following were compared among black and white women and men: demographics, comorbid illness, care processes, length of stay (LOS), hospital charges, mortality rate, and CHF readmission rate. We identified 45,894 patients (black women, 4,750; black men, 3,370; white women, 21,165; white men, 16,609). Blacks underwent noninvasive cardiac procedures more often than whites; procedure and specialty use rates were lower among women than among men. After adjusting for other patient characteristics and hospital type and location, we found race to be an important determinant of LOS (black, 10.4 days; white, 9.3 days; p = 0.0001), hospital charges (black, $13,711; white, $11,074; p = 0.0001), mortality (black-to-white odds ratio = 0.832; p = 0.003), and readmission (black-to-white odds ratio = 1.301; p = 0.0001). Gender was an important determinant of LOS (women, 9.8 days; men, 9.2 days; p = 0.0001), hospital charges (women, $11,690; men, $11,348; p = 0.02), and mortality (women-to-men odds ratio = 0.878; p = 0.0008). We conclude that race and gender influence care process and hospital-based case outcomes for patients with CHF.     

Phase II clinical and pharmacological study of pirarubicin in combination with 5-fluorouracil and cyclophosphamide in metastatic breast cancer

Doxorubicin containing combination chemotherapy regimens are widely used for treatment of breast and other cancers. However, these regimens are associated with significant toxicities including myocardial dysfunction and alopecia. Analogues of doxorubicin are being developed to reduce these side effects. We conducted a Phase II trial of an anthracycline analogue, pirarubicin, administered in combination with 5-fluorouracil and cyclophosphamide every 3 weeks, as front-line chemotherapy in women with metastatic breast cancer. Patients who had received prior anthracycline therapy were excluded. The chemotherapy doses were as follows: 5-fluorouracil (500 mg/m2 on days 1 and 8), pirarubicin (50 mg/m2 on day 1), and cyclophosphamide (500 mg/m2 on day 1). Among 40 evaluable patients treated on this protocol, a major response (partial or complete remission) was observed in 26 patients (response rate, 62%; 95% confidence interval, 46-77). The median response duration was 8 months, and median survival was 16 months. Grade III/IV myelosuppression occurred in 81% of the courses. The median cumulative pirarubicin dose was 410 (range, 90-870) mg/m2. A significant decrease in left ventricular ejection fraction occurred in 12 patients (at a median cumulative pirarubicin dose of 460 mg/m2) and led to congestive heart failure in 4 of these patients (cumulative pirarubicin doses of 500, 520, 590, and 730 mg/m2, respectively). Eleven patients underwent endomyocardial biopsy, either because they experienced a drop in left ventricular ejection fraction or because they had received a cumulative pirarubicin dose of 600 mg/m2 and were still responding to the treatment. Of these, only one biopsy was found to be more than grade 1.0 (in an individual who had received a cumulative dose of 705 mg/m2). Severe alopecia occurred in two-thirds of the patients. Pharmacokinetic studies revealed a triphasic elimination of pirarubicin with alpha, beta and gamma half-lives of 0.12, 1.44, and 33.9 h, respectively. Total clearance of drug was 4.2 liters.1 h/kg while the cumulative 24-h urinary excretion was less than 10% of the administered dose. The activity of the combination appears to be similar to doxorubicin-containing regimens, while the incidence of alopecia appears to be lower than the historical experience with doxorubicin. However, cardiotoxicity remains a significant problem.     

Peroneal osteocutaneous flap raised on reconstructed popliteal artery for delayed union following open tibial fractures

Cardiac function was assessed in long-term survivors of malignant bone tumors who were treated according to Rosen's T5 or T10 protocol, both including doxorubicin. Thirty-one patients, age 10-45 years (median age 17.8 years) were evaluated 2.3-14.1 years (median 8.9 years) following completion of treatment. Cumulative doses of doxorubicin were 225-550 mg/m2 (median dose 360). The evaluation consisted of a history, physical examination, electrocardiogram (ECG), signal averaged ECG, 24-hour ambulatory ECG, echocardiography and radionuclide angiography. Eighteen of 31 (58%) patients showed cardiac toxicity, defined as having one or more of the following abnormalities: late potentials, complex ventricular arrhythmias, left ventricular dilation, decreased shortening fraction, or decreased ejection fraction. The incidence of cardiac abnormalities increased with length of follow-up (P< or = .05). No correlation could be demonstrated between cumulative dose of doxorubicin and cardiac status, except for heart rate variability. When adjusted to body surface area, the left ventricular posterior wall thickness (LVPW index) was decreased in all patients. The incidence of doxorubicin-induced cardiotoxicity is high and increases with follow-up, irrespective of cumulative dose. Life-long cardiac follow-up in these patients is warranted. The results of our study suggest that heart rate variability and LVPW index could be sensitive indicators for cardiotoxicity.     

Impact of clinical history and electrophysiologic characterization of accessory pathways on management strategies to reduce sudden death among children with Wolff-Parkinson-White syndrome

OBJECTIVES: This study sought to determine whether the clinical and electrophysiologic criteria developed in adults also identify children with Wolff-Parkinson-White syndrome at risk for sudden death. BACKGROUND: In adults with Wolff-Parkinson-White syndrome, a shortest RR interval <220 ms during atrial fibrillation is a sensitive marker for sudden death. However, because reliance on the shortest RR interval has a low positive predictive value, the clinical history has assumed a pivotal role in assessing risk. This approach has not been evaluated in children. METHODS: We retrospectively evaluated 60 children 相似文献   

Unstable bladder and Sj?gren syndrome. Clinical case

PURPOSE: A 53-year-old female patient was treated with combined radiochemotherapy with 5-fluorouracil (5-FU) because of adenocarcinoma of the lung. She died after the 2nd day of the first course on fatal myocardial infarction. The histological evaluation of the heart revealed no severe chronic fibrosis. In our opinion the myocardial infarction was partly 5-fluorouracil-related in this case. PATIENTS AND METHODS: Published case reports on this theme were reviewed and discussed. RESULTS: The review of the literature showed a 5-FU associated cardiotoxicity in 98 cases. Most of the patients were without evidence of pre-existing myocardial disorders. The discussion about the reasons of the 5-FU-associated cardiotoxicity is still going on. Cardiotoxicity will rise up in 1.1% to 4.5% of the patients treated with 5-FU. Patients with a history of cardiac disease were at significantly increased risk for 5-FU-induced cardiotoxicity. CONCLUSION: In high-risk-patients 5-FU should not be given without electrocardiographic monitoring. The continuous infusion is better than a bolus treatment.     

Dexrazoxane cardioprotection in advanced breast cancer patients undergoing high-dose epirubicin treatment

PURPOSE: We performed a randomized trial to evaluate the cardioprotective effect of dexrazoxane (DEX) in advanced breast cancer patients (ABC) treated with high single-dose epirubicin (EPI). A secondary objective was to determine the role of radioimmunoscintigraphy (RIS) in the assessment of epirubicin cardiotoxicity. PATIENTS AND METHODS: Ninety-five patients with ABC were treated with EPI 160 mg/m2 by i.v. bolus every 3 weeks with or without DEX, 1,000 mg/m2 i.v. Cardiac monitoring included multigated radionuclide (MUGA) scan with determination of resting left ventricular ejection fraction (LVEF), and RIS with 111-Indium antimyosin monoclonal antibodies. RESULTS: The overall response rate was 69% in the EPI arm and 67% in the EPI + DEX arm; median time to response and median time to progression were identical in both arms, being 2 and 8 months, respectively. Median survival was 19 months versus 29 months (p 0.21), respectively. DEX did not appear to contribute to extracardiac EPI toxicity. Congestive heart failure occurred only in the EPI arm (2 instances). LVEF significantly decreased from baseline only in the EPI group. An abnormal tracer uptake at RIS was observed early in both arms, but the increase in heart to lung ratio was much more evident in the control group. CONCLUSIONS: DEX significantly protects against the development of high dose epirubicin cardiotoxicity apparently without evidence of an adverse impact on antitumor activity and non cardiac toxicity. RIS is a very sensitive technique in detecting anthracycline cardiac damage, but its specificity is low and cannot be considered alone a primary test for guiding anthracycline treatment.     

Correlation between scanning laser ophthalmoscope microperimetry and anatomic abnormalities in patients with subfoveal neovascularization

PURPOSE: The purpose of the study is to identify the anatomic abnormalities associated with an absolute scotoma and the location and stability of fixation in patients with subfoveal neovascularization in age-related macular degeneration, presumed ocular histoplasmosis syndrome, and other disorders. METHODS: Scanning laser ophthalmoscope microperimetry was superimposed on color fundus photographs and fluorescein angiograms of 21 eyes with subfoveal neovascular membranes secondary to age-related macular degeneration (14 eyes) and presumed ocular histoplasmosis syndrome (7 eyes). The authors determined the location and the area occupied by the absolute scotoma and each of the following subretinal lesions: subretinal hemorrhage, neurosensory retinal detachment, retinal pigment epithelial (RPE) atrophy, RPE hyperplasia, atrophy of the choriocapillaris, hard exudates, and the subfoveal neovascular membrane. The area of absolute scotoma determined by scanning laser ophthalmoscope microperimetry was superimposed on the anatomic lesions. The authors calculated the relative risk ratio (RR) of an absolute scotoma occurring in regions corresponding to each anatomic abnormality, and determined the preferred location and stability of fixation in each eye. RESULTS: An absolute scotoma was present in areas of chorioretinal scar (RR = 107.61), RPE atrophy (RR = 9.97), subretinal hemorrhage (RR = 2.88), and the neovascular membrane (RR = 1.86). Fixation was stable in all patients with presumed ocular histoplasmosis syndrome but only 29% of patients with age-related macular degeneration. Fifty-five percent of patients with stable fixation fixated over an area of RPE hyperplasia. CONCLUSION: The relative risk of an absolute scotoma is highest over areas of chorioretinal scars, RPE atrophy, subretinal hemorrhage, and the neovascular membrane. Fixation is more stable in patients with subfoveal neovascularization from presumed ocular histoplasmosis syndrome than with age-related macular degeneration and frequently is present over an area of RPE hyperplasia.     

Differential effects of BMI on diabetes risk among black and white Americans

OBJECTIVE: To determine whether the associations of BMI and fat distribution with diabetes risk are modified by race. RESEARCH DESIGN AND METHODS: Data from the National Health and Nutrition Examination Survey, Epidemiologic Follow-up Study (1971-1992), were used to investigate potential interactions of BMI and fat distribution with race. Incident diabetes was defined by self-report of physician-diagnosed diabetes, hospital and nursing home discharge records, and death certificates. RESULTS: Among the 1,531 black and 9,852 white subjects who were nondiabetic at baseline, 1,139 (10.0%) developed diabetes during 20 years of follow-up. Although the cumulative risk of diabetes increased with baseline BMI in all four race-sex groups, the sex-specific odds ratios (ORs) for black:white subjects decreased with increasing BMI. In particular, for BMI of 22 kg/m2, the OR of diabetes for black:white individuals was 1.87 and 1.76 (P < 0.01) for men and women, respectively; for BMI of 32 kg/m2, the OR decreased to 0.99 and 1.20 (NS) for men and women, respectively. Skinfold ratio was also associated with increased diabetes risk in all race-sex groups, but did not modify the association between race and diabetes. CONCLUSIONS: These findings suggest that the effect of BMI on diabetes risk is different for black and white Americans, with a larger risk for blacks than whites at low BMI and an equivalent risk for both groups at high BMI. A lower degree of visceral adiposity among blacks at higher BMI or a greater impact of visceral adiposity among blacks at low BMI may help explain the interaction of race and BMI on diabetes risk.     

Use and misuse of oral contraceptives: risk indicators for poor pill taking and discontinuation

The contraceptive efficacy of oral contraceptives (OCs) depends on their proper and continued use, particularly with lower estrogen preparations. However, few studies have examined why women miss pills or discontinue OCs, and those that do tend to be small and to focus on adolescents. To address the issues of poor OC compliance and early OC discontinuation, we analyzed OC use in a convenience sample of 6,676 women between the ages of 16 and 30 from Denmark, France, Italy, Portugal, and the United Kingdom. Logistic regression was used to examine the independent effect of each factor. Poor compliance was associated with a lack of established routine for pill-taking (relative risk [RR] = 3.3), failure to read and understand written materials that came with the OC package (RR = 2.2), not receiving adequate information or help about OCs from their health care provider (RR = 1.5), and occurrence of certain side effects, including hirsutism (RR = 2.1), nausea (RR = 1.4), bleeding irregularities (RR = 1.3), and breast tenderness (RR = 1.2). Women who were inconsistent OC users, missing one or more pills per cycle, were almost three times as likely to experience an unintended pregnancy while using OCs than were women who took their OCs consistently. Factors that predicted early discontinuation (women who wished to continue contraceptive protection but discontinued OC use) were primarily side effects, including nausea (RR = 2.1), bleeding (RR = 1.9), breast tenderness (RR = 1.8), mood changes (RR = 1.8), and weight gain (RR = 1.4).(ABSTRACT TRUNCATED AT 250 WORDS)     

Child health and the social environment of white and black children

Both poverty and other factors associated with race are related to child health. However, the mechanisms of these relationships have not been adequately specified. The purpose of this study was to explore the relationship of the social environment to child health status in black and white children and further, to explore whether the patterns of the effects of social class were different by race. This study provides further evidence that the social environment is strongly associated with child health status. Several risk factors are similar for both white and black children: mothers who view their own health as fair or poor are much more likely to rate their children in poor health. The presence of childhood chronic medical conditions is independently associated with poor health status regardless of race. However, the relative importance of several social risks for poor health status differs between white and black children. Specifically, while low family income is a consistent risk factor for poor health among white children, low income alone is not a risk factor for black children. Among black children, other social risks that are associated with poverty, such as low maternal education and a mother's perception of her own health as poor, increased the risk of poorer health in the child.     

Antimicrobial resistance: dentistry''s role

OBJECTIVES: To investigate the following questions. (1) Is silica dust on its own, without the presence of silicosis, associated with an increased risk of pulmonary tuberculosis (PTB) in workers exposed to silica dust? (2) In the absence of silicosis is the excess risk dose related? (3) What is the predominant chronological sequence between the development of PTB and the development of silicosis after the end of exposure to dust? METHODS: A cohort of 2255 white South African gold miners has been followed up from 1968 to 1971, when they were 45-55 years of age, to 31 December 1995 for the incidence of PTB. During the follow up 1592 (71%) men died. Of these, 1296 (81%) had a necropsy done at the National Centre for Occupational Health (NCOH) to determine the presence of silicosis and PTB. The incidence of PTB in the cohort was studied relative to cumulative exposure to dust and the onset of silicosis. For the miners with necropsy, the incidence for PTB was studied relative to the severity of silicosis found at necropsy. RESULTS: There were 115 subjects who developed PTB. The total person-years of follow up was 39,319. For the whole cohort, the factors associated with increased risk of PTB were cumulative exposure to dust (mg/m3.y) (the adjusted rate ratio (RR) 1.07; (95% confidence interval (95% CI) 1.04 to 1.10)), silicosis diagnosed radiologically (3.96 (2.59 to 6.06)), and tobacco pack-years (1.02 (1.01 to 1.03)). The RR (95% CI) for PTB increased with increasing quartiles of cumulative exposure to dust 1.0, 1.51 (0.78 to 2.91), 2.35 (1.28 to 4.32), and 3.22 (1.75 to 5.90). In miners who did not have radiologically diagnosed silicosis (n = 1934, PTB = 74), the adjusted RR (95% CI) for PTB and cumulative exposure to dust was 1.10 (1.06 to 1.13), and increased with quartiles of cumulative exposure to dust as 1.00, 1.46 (0.70 to 3.03), 2.67 (1.37 to 5.23), and 4.01 (2.04 to 7.88). For the subjects who had a necropsy (n = 1296, PTB = 70), the adjusted RR (95% CI) for PTB increased with the severity of silicosis found at necropsy; 1.0 for no silicosis, 1.88 (0.97 to 3.64) for negligible, 2.69 (1.35 to 5.37) for slight, and 2.30 (1.16 to 4.58) for moderate or marked silicosis. For subjects who had a necropsy and no silicosis (n = 577, PTB = 18), the adjusted RR (95% CI) increased slightly with quartiles of cumulative dust 1.0, 1.11 (0.31 to 4.00), 1.42 (0.43 to 4.72), and 1.38 (0.33 to 5.62). CONCLUSION: Exposure to silica dust is a risk factor for the development of PTB in the absence of silicosis, even after exposure to silica dust ends. The risk of PTB increases with the presence of silicosis, and in miners without radiological silicosis, with quartiles of exposure to dust. The severity of silicosis diagnosed at necropsy was associated with increasing risk of PTB and even < 5 nodules--that is, undetectable radiologically--was associated with an increased risk of PTB. The diagnosis of PTB was on average 7.6 years after the end of exposure to dust, at around 60 years of age. The onset of radiological silicosis preceded the diagnosis of PTB in 90.2% of the cases with PTB who had silicosis. The results have implications for medical surveillance of workers exposed to silica dust after the end of exposure.     

Flavonol and chalcone ester glycosides from Bidens andicola

OBJECTIVES: To examine the effect of black race and acute (negative life events) and chronic (lack of social support) psychological stress on the risk of herpes zoster in late life. DESIGN: A population-based, prospective cohort study. SETTING: Central North Carolina. PARTICIPANTS: Duke Established Populations for Epidemiological Studies of the Elderly, a stratified probability sample of community-dwelling persons more than 65 years of age. MEASUREMENTS: Interviewers administered a comprehensive health survey to the participants in 1986-1987 (P1, n = 4162), 1989-1990 (P2, n = 3336), and 1992-1994 (P3, n = 2568). Incident cases of zoster between P1 and P2 and P2 and P3 served as the dependent variable. Hypothesis-testing variables included race, negative life events, and five measures of social support. Control variables included age, sex, education, cancer, chronic diseases, basic ADLs, instrumental ADLs, depression, self-rated health, hospitalization, and cigarette smoking. Statistical analyses employed chi-square tests and proportional hazards model. RESULTS: At baseline, the sample had a mean age of 73.6 years and was 55% black, 45% white, and 65% female. There were 65 cases of zoster between P1 and P2 and 102 cases of zoster between P2 and P3. From P1 to P2, 1.4% of blacks and 3.4% of whites developed zoster (P < .001). From P2 to P3, 2.9% of blacks and 7.5% of whites developed zoster (P < .001). After controlling for the above variables, blacks were significantly less likely to develop zoster (adjusted risk ratio = 0.35; 95% confidence interval (CI), 0.24-0.51; P < .001). Negative life events increased the risk of zoster, but the result was borderline for statistical significance (adjusted RR = 1.38, 95% CI 0.96-1.97; P = .078). No measures of social support were significantly associated with zoster. CONCLUSION: Black race decreased the risk of zoster in late life significantly. Measures of stress were not significantly related to zoster, but study limitations preclude definitive conclusions. Future research should focus on these factors in larger samples and different populations.     

Race, treatment, and survival among colorectal carcinoma patients in an equal-access medical system

BACKGROUND: The aim of this study was to assess the influence of race on the treatment and survival of patients with colorectal carcinoma. METHODS: This retrospective cohort study included all white or black male veterans given a new diagnosis of colorectal carcinoma in 1989 at Veterans Affairs Medical Centers nationwide. After adjusting for patient demographics, comorbidity, distant metastases, and tumor location, the authors determined the likelihood of surgical resection, chemotherapy, radiation therapy, and death in each case. RESULTS: Of the 3176 veterans identified, 569 (17.9%) were black. Bivariate analyses and logistic regression revealed no significant differences in the proportions of patients undergoing surgical resection (70% vs. 73%, odds ratio 0.92, 95% confidence interval 0.74-1.15), chemotherapy (23% vs. 23%, odds ratio 0.99, 95% confidence interval 0.78-1.24), or radiation therapy (17% vs. 16%, odds ratio 1.10, 95% confidence interval 0.85-1.43) for black versus white patients. Five-year relative survival rates were similar for black and white patients (42% vs. 39%, respectively; P=0.16), though the adjusted mortality risk ratio was modestly increased (risk ratio 1.13, 95% confidence interval 1.01-1.28). CONCLUSIONS: Overall, race was not associated with the use of surgery, chemotherapy, or radiation therapy in the treatment of colorectal carcinoma among veterans seeking health care at Veterans Affairs Medical Centers. Although mortality from all causes was higher among black veterans with colorectal carcinoma, this finding may be attributed to underlying racial differences associated with survival. This study suggests that when there is equal access to care, there are no differences with regard to race.     

Breathing pattern and additional work of breathing in spontaneously breathing patients with different ventilatory demands during inspiratory pressure support and automatic tube compensation

OBJECTIVE: To identify predictors of hypoglycemic and hyperglycemic episodes in hospitalized patients with diabetes with special attention to the effectiveness of sliding scale insulin regimens. DESIGN: Prospective cohort study. SETTING: Urban university hospital. PARTICIPANTS: One hundred seventy-one adults with diabetes mellitus as a comorbid condition admitted consecutively to medical inpatient services during a 7-week period. MEASUREMENTS: Demographic, clinical, and laboratory data from inpatient medical records. MAIN OUTCOMES: Rates of hypoglycemic (capillary blood glucose, < or = 3.3 mmol/L [< or = 60 mg/dL]) and hyperglycemic (capillary blood glucose, > or = 16.5 mmol/L [> or = 300 mg/ dL]) episodes. RESULTS: Of the patients, 23% experienced hypoglycemic episodes, and 40% experienced hyperglycemic episodes. The overall rates of hypoglycemic and hyperglycemic episodes were 3.4 and 9.8 per 100 capillary blood glucose measurements, respectively. Independent predictors of hypoglycemic episodes included African American race (relative risk [RR], 2.13) and low serum albumin level (RR, 1.92 per 100-g/L decrease); corticosteroid use was associated with a reduced risk of hypoglycemic episodes (RR, 0.32; P < .05). Independent predictors of hyperglycemic episodes included female gender (RR, 1.67), severity of illness (RR, 1.22 per 10 Acute Physiology and Chronic Health Evaluation III units), severe diabetic complications (RR, 2.32), high admission glucose level (RR, 1.33 per 5.5 mmol/L), admission for infectious disease (RR, 2.14), and corticosteroid use (RR, 3.74; P < .05). Of 171 patients, 130 (76%) were placed on a sliding scale insulin regimen. When used alone, sliding scale insulin regimens were associated with a 3-fold higher risk of hyperglycemic episodes compared with individuals following no pharmacologic regimen (RRs, 2.85 and 3.25, respectively; P < .05). CONCLUSIONS: Suboptimal glycemic control is common in medical inpatients with diabetes mellitus. The risk of suboptimal control is associated with selected demographic and clinical characteristics, which can be ascertained at hospital admission. Although sliding scale insulin regimens are prescribed for the majority of inpatients with diabetes, they appear to provide no benefit; in fact, when used without a standing dose of intermediate-acting insulin, they are associated with an increased rate of hyperglycemic episodes.     

Paclitaxel with mitoxantrone, fluorouracil, and high-dose leucovorin in the treatment of metastatic breast cancer: a phase II trial

PURPOSE: Paclitaxel is a highly active single agent in the treatment of breast cancer. However, its optimal incorporation into combination regimens awaits definition. In this phase II study, we added paclitaxel, administered by 1-hour infusion, to a previously described combination regimen that included mitoxantrone, fluorouracil (5-FU), and high-dose leucovorin (NFL). PATIENTS AND METHODS: Forty-six patients with metastatic breast cancer received the following regimen as first- or second-line treatment: paclitaxel 135 mg/m2 by 1-hour intravenous (i.v.) infusion on day 1, mitoxantrone 10 mg/m2 by i.v. bolus on day 1, 5-FU 350 mg2/m by i.v. bolus on days 1, 2, and 3, and leucovorin 300 mg i.v. over 30 to 60 minutes immediately preceding 5-FU on days 1, 2, and 3. Courses were administered at 3-week intervals for a total of eight courses in responding patients. RESULTS: Twenty-three of 45 assessable patients (51%) had major responses. Previous chemotherapy, and in particular previous treatment with doxorubicin, did not affect response rate. The median response duration was 7.5 months. Myelosuppression was moderately severe, with 76% of courses resulting in grade 3 or 4 leukopenia. Hospitalization for treatment of fever during neutropenia was required in 13% of courses, and two patients died as a result of sepsis. Two patients developed severe congestive heart failure after a large cumulative anthracycline dose. CONCLUSION: This combination regimen was active as first- or second-line therapy for metastatic breast cancer, although its activity compared with other combination regimens or with paclitaxel alone is unclear. Myelosuppression was more severe than anticipated based on previous results with the NFL regimen or with paclitaxel administered at this dose and schedule as a single agent. The infrequent development of cardiotoxicity in these patients suggests that the paclitaxel/mitoxantrone combination may not share the problems previously reported with the paclitaxel/doxorubicin combination.