Advantages of concurrent biochemotherapy modified by decrescendo interleukin-2, granulocyte colony-stimulating factor, and tamoxifen for patients with metastatic melanoma.

PURPOSE: Concurrent biochemotherapy results in high response rates but also significant toxicity in patients with metastatic melanoma. We attempted to improve its efficacy and decrease its toxicity by using decrescendo dosing of interleukin-2 (IL-2), posttreatment granulocyte colony-stimulating factor (G-CSF), and low-dose tamoxifen. PATIENTS AND METHODS: Forty-five patients with poor prognosis metastatic melanoma were treated at a community hospital inpatient oncology unit affiliated with the John Wayne Cancer Institute (Santa Monica, CA) between July 1995 and September 1997. A 5-day modified concurrent biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo IL-2, interferon alfa-2b, and tamoxifen was repeated at 21-day intervals. G-CSF was administered beginning on day 6 for 7 to 10 days. RESULTS: The overall response rate was 57% (95% confidence interval, 42% to 72%), the complete response rate was 23%, and the partial response rate was 34%. Complete remissions were achieved in an additional 11% of patients by surgical resection of residual disease after biochemotherapy. The median time to progression was 6.3 months and the median duration of survival was 11.4 months. At a maximum follow-up of 36 months (range, 10 to 36 months), 32% of patients are alive and 14% remain free of disease. Decrescendo IL-2 dosing and administration of G-CSF seemed to reduce toxicity, length of hospital stay, and readmission rates. No patient required intensive care unit monitoring, and there were no treatment-related deaths. CONCLUSION: The data from this study indicate that the modified concurrent biochemotherapy regimen reduces the toxicity of concurrent biochemotherapy with no apparent decrease in response rate in patients with poor prognosis metastatic melanoma.

Comparison of the natural history of new onset and exacerbated chronic ischemic heart disease. The Chest Pain Study Group.

To compare the natural history of patients with new onset ischemic heart disease with that of patients with exacerbations of chronic ischemic heart disease, short- and long-term outcomes of 3,465 emergency room patients with acute ischemic heart disease at four community and three university hospitals were evaluated. Acute myocardial infarction was diagnosed in 598 (33%) of the 1,835 patients with a prior history of infarction or angina and 934 (57%) of the 1,630 without such a history (p less than 0.001). Patients with new onset ischemic heart disease with acute myocardial infarction were more likely than patients with infarction and exacerbated chronic ischemic heart disease to have Q wave infarction (57% versus 36%) and to receive thrombolytic therapy (11% versus 5%); they also had higher maximal creatine kinase levels (1,088 +/- 1,299 versus 733 +/- 906 U/liter) (p less than 0.0001 for all three). After adjustment for differences in clinical presentation and initial triage, patients with new onset ischemic heart disease with acute myocardial infarction were less likely than the comparison group to have congestive complications (odds ratio 0.63, 95% confidence interval 0.47 to 0.84, p less than 0.01) but not less likely to have arrhythmic, ischemic or overall complications. Among patients with angina without acute myocardial infarction, patients with new onset ischemic heart disease were less likely to have recurrent ischemic pain and congestive heart failure. In multivariate analysis of long-term follow-up data on 457 patients from one hospital, patients with new onset ischemic heart disease had better cardiovascular survival rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute chest pain in the emergency room. Identification and examination of low-risk patients.

Clinical and laboratory data from 596 patients who came to an emergency room complaining of chest pain indicated that no single variable could identify low-risk patients as well as a normal ECG. A combination of three variables--sharp or stabbing pain, no history of angina or myocardial infarction, and pain with pleuritic or positional components or pain that was reproduced by palpation of the chest wall--defined a very-low-risk group in which ECGs did not add accuracy to the evaluation and were potentially misleading; however, only 48 patients (8%) fell into this category. Standard cardiac enzyme levels were of almost no use as an emergency room indicator of myocardial infarction. These findings emphasize the difficulty of identifying patients at low risk for myocardial infarction or unstable angina in the emergency room without consideration of many factors from the history, the physical examination, and the ECG.

Evaluation of creatine kinase and creatine kinase-MB for diagnosing myocardial infarction. Clinical impact in the emergency room.

We prospectively studied the performance of emergency room strategies using a single sampling of total creatine kinase (CK) only and total CK with, if total CK levels were elevated, CK-MB levels in 639 patients with acute chest pain, including 386 patients who were admitted and 253 patients who were discharged. Acute myocardial infarction was diagnosed in 104 patients and excluded in 535. An elevated total CK level had a sensitivity of only 38% and specificity of only 80%, whereas a CK-MB level over 5% of an elevated total CK level had a sensitivity of only 34% and specificity of 88%. The sensitivities of both CK and CK-MB were higher in patients who arrived more than four hours after the onset of symptoms, and, in this population, the strategy using CK-MB performed significantly better than the strategy using total CK alone. Since a very positive CK-MB in a low-risk patient can greatly raise the probability of myocardial infarction, future strategies using CK-MB may have a role in selected subsets in determining which patients should not be sent home. However, the sensitivity of a single sampling of CK and CK-MB is too low for these assays to be used to exclude myocardial infarction in the emergency room or to be used as the rationale for deciding not to admit a patient.

Identification and preliminary validation of predictors of major bleeding in hospitalized patients starting anticoagulant therapy.

Among 617 hospitalized patients who started long-term anticoagulant therapy, major bleeding developed before discharge in 28 (5 percent) and minor bleeding in another 38 (6 percent), with daily incidence rates of 0.4 and 0.5 percent, respectively. The most common site of bleeding was gastrointestinal, and one patient died from bleeding. Four independent risk factors for major in-hospital bleeding were identified and weighted using multivariate discriminant analysis in a randomly chosen group of 411 patients: co-morbid conditions other than the indication for anticoagulant therapy (specific signs of heart, liver, or kidney dysfunction, cancer, and severe anemia); the use of heparin to begin therapy in patients age 60 years or older; the intensity of therapy (measured by the maximal prothrombin time or partial thromboplastin time); and liver dysfunction that worsened during treatment. These findings were validated in an independent testing group of 206 patients; the risk factors identified 151 patients at low (1 percent) risk of major bleeding, 33 at moderate (6 percent) risk, and 22 at high (23 percent) risk. The accuracy and clinical impact of this prediction rule should be evaluated further in other hospitals.

Outcomes in patients with myocardial infarction who are initially admitted to stepdown units: data from the Multicenter Chest Pain Study.

PURPOSE: To assess whether the admission of patients with chest pain to a stepdown unit would jeopardize the outcome of those patients who ultimately "ruled in" for a myocardial infarction. PATIENTS AND METHODS: We compared the risk of an adverse outcome in initially uncomplicated, "rule-out myocardial infarction" patients who were admitted directly to a stepdown unit (n = 58) or to a coronary care unit (n = 409) at 6 hospitals and who then ultimately "ruled in" for a myocardial infarction. RESULTS: An adverse outcome (death, serious complication, or invasive intervention) occurred in 16 (28%) stepdown unit patients compared with 159 (39%) coronary care unit patients. Among patients eligible for initial care in either location, the risk of an adverse outcome after controlling for clinical characteristics was similar in the two groups using each of two different multivariate approaches. CONCLUSION: Although our study was not of sufficient size to exclude the possibility of a small benefit from initial triage to a coronary care unit, our data suggest that (1) admission of initially uncomplicated chest pain patients with a relatively low probability of acute myocardial infarction to a stepdown unit does not seriously jeopardize those who eventually "rule in" for myocardial infarction; and (2) larger observational or randomized studies, which could reduce the residual possibility of somewhat higher risk in the stepdown unit, would be ethical to perform.

Effect of transgenic overexpression of NR2B on NMDA receptor function and synaptic plasticity in visual cortex.

The NMDA receptor (NMDAR) is a heteromer comprised of NR1 and NR2 subunits. Mice that overexpress the NR2B subunit exhibit enhanced hippocampal LTP, prolonged NMDAR currents, and improved memory ( Tang et al., 1999). In the current study, we explored visual cortex plasticity and NMDAR function in NR2B overexpressing transgenic mice. Unlike the hippocampus, in vitro synaptic plasticity of the visual cortex was unaltered by NR2B overexpression. Consistent with the plasticity findings, NMDAR excitatory postsynaptic current (EPSC) durations from layer 2/3 pyramidal cells were similar in wild-type (wt) and transgenic (tg) mice. Furthermore, temporal summation of NMDAR EPSCs to 10, 20, and 40 Hz stimulation did not differ between cells from wt and tg mice. Finally, although in situ studies clearly demonstrate overexpression of NR2B mRNA in visual cortex, we failed to observe a significant elevation in the synaptic expression of NR2B protein. We conclude that the synaptic ratio of NR2B over NR2A in the NMDA receptor complex in the visual cortex is not significantly influenced by the transgene overexpression. These data suggest that mRNA availability is not a limiting factor for the synthesis of NR2B protein in the visual cortex, and support the hypothesis that levels of NR2A, rather than NR2B, normally determine the subunit composition of NMDARs in visual cortex.

Outcome of patients who were admitted to a new short-stay unit to "rule-out" myocardial infarction.

For emergency room patients with a low probability of acute myocardial infarction, we established a new short-stay coronary observation unit, a 2-bed nonintensive care unit with telemetry monitoring adjacent to the emergency room. Of 512 consecutive admissions to the coronary observation unit, 425 (83%) were discharged home without evidence of acute myocardial infarction or serious complications (mean length of stay, 1.2 days; median length of stay, 1 day); 87 (17%) were transferred to other hospital beds. The rate of acute myocardial infarction was 3%. No deaths and only 1 serious complication occurred in the coronary observation unit. At 6 month follow-up, the cardiac survival rate was 99% for patients sent home directly from this unit. It is concluded that the coronary observation unit is safe and adequate for ruling out acute myocardial infarction in a defined subset of patients. Short-stay units, however, encourage early discharges which, when premature, may miss patients who are at risk of having complications shortly thereafter. Strategies such as mandatory but expeditious predischarge stress testing to encourage early but not premature discharge may augment the efficiency of coronary observation units.

Diagnostic implications for myocardial ischemia of the circadian variation of the onset of chest pain.

To determine whether the occurrence of chest pain is randomly distributed during the day and to study whether the time of onset is useful in discriminating among causes of chest pain, patients older than 30 years who presented to 7 emergency departments with a chief complaint of chest pain unexplained by trauma or chest x-ray abnormalities were studied. A total of 7,759 patients presented during the study period; of these, 3,990 presented within 6 hours of the onset of pain and were included in the primary analysis. Chest pain caused by acute myocardial infarction, unstable angina pectoris and stable angina pectoris was more likely to begin during the period from 6 AM to noon than would be expected if the onset were uniformly distributed during the day (relative risks 1.15, 1.29 and 1.32, respectively), but chest pain that was caused by nonischemic cardiac causes and by noncardiac causes was also more likely to begin during the same time period (relative risks 1.28 and 1.17). Although chest pain from coronary arterial causes had a distinct circadian variation, the time of onset of pain was not a helpful criterion for determining the cause of chest pain.

Clinical characteristics and outcome of acute myocardial infarction in patients with initially normal or nonspecific electrocardiograms (a report from the Multicenter Chest Pain Study).

To determine the prevalence and characteristics of acute myocardial infarction (AMI) patients who present to emergency departments with normal or nonspecific electrocardiograms (ECGs), data were analyzed from 7,115 consecutive patients in the Multicenter Chest Pain Study. AMI patients with normal or nonspecific initial ECGs (n = 107) were less likely to have a past history of coronary artery disease or to be diaphoretic on presentation (p less than 0.01) than AMI patients with initial ECGs highly suggestive of AMI (n = 811). The overall probability of AMI among patients with chest pain and initially normal or nonspecific ECGs was 3%, but ranged from less than 1 to 17% depending on the patient's age and sex and whether the patient had pressure-type pain or pain radiating to the shoulder, neck or arms. Among initially admitted patients, the time elapsed between onset of pain and presentation was similar in both groups. However, the time between onset of pain and definitive diagnosis of AMI by enzymes or clinical course was longer in patients with initially normal or nonspecific electrocardiograms (8.3 vs 7.5 hours, p less than 0.05), their peak creatine kinase levels were lower (mean 643 vs 1,032 mg/dl, p less than 0.001) and their mortality was slightly lower (6 vs 12%, p = 0.10). These findings suggest that AMI patients with initially normal or nonspecific ECGs may have a less severe short-term clinical outcome.

Comparison of clinical presentation of acute myocardial infarction in patients older than 65 years of age to younger patients: the Multicenter Chest Pain Study experience.

To assess whether the manifestations of acute ischemic heart disease in the elderly are less typical than in younger patients, the presenting clinical features and their associated relative risks for acute myocardial infarction (AMI) were compared in 2,625 patients greater than or equal to 65 years of age and 5,109 patients less than 65 years of age. These patients were evaluated for acute chest pain in the emergency departments of 7 hospitals. The same features were associated with increased relative risks for AMI in younger and elderly patients. The relative risks among older patients, however, were consistently closer to 1.0 for classic features, including male gender, pressure-like quality of pain, substernal location, typical pattern of pain radiation and electrocardiographic evidence of ischemia or AMI. Analyses for the endpoint "acute ischemic heart disease" (i.e., AMI or unstable angina) yielded similar findings. Elderly patients were more likely to be admitted to the hospital (56 vs 35%; p less than 0.0001) and to the coronary care unit (37 vs 23%; p less than 0.0001) in the absence of either AMI or unstable angina. These data support the hypothesis that diagnosis of acute chest pain is especially difficult in elderly patients.

Clinical characteristics and natural history of patients with acute myocardial infarction sent home from the emergency room.

In a prospective multicenter investigation of emergency room patients with acute chest pain, physicians admitted 96% of patients with acute myocardial infarction (AMI) and discharged 4%. Of 35 patients who were sent home with AMI, only 11 (31%) returned to the same hospital because of persistent symptoms. Compared with a control group of 105 randomly selected patients with AMI who were admitted from the emergency room, patients in whom AMI was missed were significantly younger, had less typical symptoms and were less likely to to have had prior AMI or angina or to have electrocardiographic evidence of ischemia or infarction not known to be old. Despite the less typical presentations of patients in whom AMI was missed, after controlling for age and sex, the short-term mortality rate was significantly higher among patients in whom AMI was missed but in whom it was detected through our follow-up procedures than in admitted AMI patients. As determined by independent reviewers, 49% of the missed AMIs could have been diagnosed through improved electrocardiographic reading skills or by admission of patients with recognized ischemic pain at rest or ischemic electrocardiographic changes not known to be old.

Hemodynamics of the carotid-artery circulation in the elderly "dizzy" patient.

One hundred and one consecutive patients complaining of dizziness were assessed by noninvasive carotid-artery testing, including oculoplethysmography, supraorbital directional Doppler and direct carotid flow Doppler. Hemodynamically significant carotid disease was found in 8 of 34 patients with the nonspecific complaint of "lightheadedness," in 4 of 21 patients with syncope, in 3 of 12 patients with vertebrobasilar insufficiency, and in 7 of 27 patients with associated focal cerebral signs or symptoms. None of 7 patients with vertigo alone were affected. In summary, 21 of the 101 patients with dizziness had hemodynamically significant obstruction to flow in the carotid-artery circulation. These findings suggest that in a fairly large proportion of patients complaining of dizziness, the symptoms may be the result of decreased cerebral perfusion due to carotid-artery occlusive disease. In these patients, noninvasive carotid-artery testing appears to be useful in identifying those with significant obstruction to blood flow in the carotid-artery circulation.

Description of a universal data entry and retrieval program for vascular surgeons.

Until recently, vascular surgeons have had to make judgments based on an impression of their experiences rather than upon the actual facts. Presently, with the simplified and less costly use of computers, the establishment of a computerized data base is feasible. Our goal had been to develop a system suitable for micro- or minicomputers which can be programmed in ordinary English and, once in place, requires essentially no knowledge of computers or computer programming for its successful use. Such a data base could put to an end the comparison of series that are truly incomparable because of differences in data classification and presentation. For example, in the case of a femoropopliteal bypass, which eventuates in a successful thrombectomy, some call it a success, some call it a failure, and some list it as both a success and failure. Many ignore the thrombectomy entirely and choose to place the final result in the plus category of "limb salvage." One seemingly insurmountable problem has been that because practice patterns differ, it has been necessary to design individual computer programs. A programmer has been required to write each of these programs, with consequent great expense and delay. While there are programs available for establishing a data base, they largely have required the use of large computers. Using such a computer implies a time sharing system with frustrations in regard to both availability and ease of use.

Treatment of vaginal candidiasis in pregnant women.

Pregnancy creates a climate favorable to the growth of Candida albicans, and this yeast often is difficult to eradicate in pregnant women. Miconazole nitrate administered intravaginally has been found to achieve comparable therapeutic and mycological cure rates in both pregnant and nonpregnant women. A number of clinical studies, using rigid definitions of cure, have demonstrated that miconazole nitrate is significantly better than nystatin, clotrimazole, and butoconazole, a new imidazole derivative, in treating vaginal candidiasis during gestation.

Terconazole--a new antifungal agent for vulvovaginal candidiasis.

Terconazole is a new broad-spectrum antifungal agent for the treatment of vulvovaginal candidiasis. Instead of an imidazole structure, terconazole contains a triazole ring, a structure developed specifically to improve antifungal activity. Clinical studies of this antifungal agent have involved 5,500 women worldwide and a number of terconazole formulations, including 80-mg vaginal suppositories and 0.4% vaginal cream. The highlights of several large, major studies are discussed in this review article. In European studies, mycologic cure rates for terconazole regimens approached or exceeded 90%. Speed of action was rapid, and relapse rates were low. In double-blind, multicenter studies conducted in the United States, clinical cure rates for 0.4% terconazole cream ranged from 86% to 96% and microbiologic cure rates from 77% to 91% at 8 to 10 days after therapy. Most patients remained free of positive signs and symptoms and microbiologic evidence of infection at 30 to 35 days posttherapy. Symptomatic relief tended to be more rapid for patients treated with 0.4% terconazole cream than for those treated with 2.0% miconazole nitrate cream. In US studies of 80-mg terconazole suppositories, clinical cure rates 8 to 10 days after therapy were between 89% and 92%, and microbiologic cure rates were between 80% and 85%. Relapse rates were also low with this form of therapy. No statistically significant differences were found between three days of treatment with 80-mg terconazole suppositories and seven days of treatment with 100-mg miconazole nitrate suppositories. This research demonstrates that terconazole is a fast-acting, highly effective, well-tolerated therapy for vulvovaginal candidiasis.

Do endocrines play an etiological role in diabetic and nondiabetic sexual dysfunctions?

Sexually dysfunctional diabetic and nondiabetic males were compared with a group of normal controls using different endocrinological, psychophysiological, and psychological parameters. One hundred male subjects participated in this study: 47 diabetics with sexual dysfunction (DD), 31 nondiabetics with sexual dysfunction (NDD), and 22 normal controls (C). They were evaluated by an internist (physical examination and medical history), a psychologist (psychological and sexual functioning tests), a psychiatrist (psychiatric history and mental status examination), a urologist (genitourinary physical examination), and an endocrine biochemist (evaluation of endocrine factors). Additionally, subjects were evaluated for nocturnal penile tumescence (NPT) during three nights in the sleep laboratory to obtain a differential diagnosis of impotence, that is, psychogenic vs. organic. Both sexually dysfunctional groups showed significant differences on several measures in the psychological and psychophysiological evaluations. There were also significant differences between these two groups and the control group. Plasma levels of total testosterone and serum levels of prolactin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) showed no significant differences among the three groups, but there were some significant correlations between the endocrine and psychological measures. No significant correlations were found between the endocrine and psychophysiological measures.

Exposure to magnetic resonance imaging does not produce taste aversion in rats.

A taste aversion test was used to evaluate possible toxic effects of magnetic resonance imaging (MRI). Thirty male Sprague-Dawley rats were randomly assigned to four groups: Group One (n = 10) received 30 minutes exposure inside the MRI scanner; Group Two (n = 10) received a sham exposure to the MRI scanner; Group Three (n = 5) was injected with 0.15 M lithium chloride; and Group Four (n = 5) was injected with vehicle. All groups were given 10 minutes access to a 0.1% saccharin solution immediately prior to their respective treatment. The rats treated with lithium chloride displayed a taste aversion to the saccharin solution upon subsequent testing over an eight day period. The two control groups (Two and Four) and the rats exposed to MRI did not display any aversion to the saccharin solution. These results are compared to other studies that have shown that magnetic fields can influence biological systems.

Data assessing the usefulness of screening obstetrical ultrasonography for detecting fetal and placental abnormalities in uncomplicated pregnancy: effects of screening a low-risk population.

To investigate the usefulness of screening in low-risk populations, the authors evaluated the yield of ultrasonography for detecting abnormalities in 678 clinically uncomplicated pregnancies. The yield of ultrasonography in high-risk women who were referred for amniocentesis was remarkably similar to the yield in other women. All four diagnoses of twins were correct, but overall only six of 12 initial ultrasound diagnoses of fetal demise or fetal anomalies were confirmed at delivery. Of the eight major fetal anomalies present at delivery, including two cases of Down's syndrome, three had been detected by ultrasonography; none of the nine minor anomalies had been detected, usually because they were too small or might be detectable only at a later gestational age. Although ultrasonography may have a nearly perfect predictive value for certain anomalies, on average, in this study, positive ultrasonography increased the probability of an adverse outcome of pregnancy from 5.3% to 36%, while a normal ultrasound examination decreased the probability to 4.4%. These data, which emphasize the implications of screening a low-risk population, suggest that recommendations regarding routine screening obstetrical ultrasonography should await sufficiently large controlled trials demonstrating consistent clinical benefit, in terms of reassurance or of providing a baseline for future comparison or in terms of improved outcome at a reasonable cost.

Evaluation of two rapid methods for the detection of herpes simplex virus antigen in patient specimens.

An indirect immunofluorescent antibody procedure (IFA) for the detection and typing of herpes simplex virus (HSV) and an enzyme-linked immunosorbent assay (ELISA) procedure were compared with conventional viral culture. Specimens for culture and ELISA were inoculated into serum free viral transport medium (VTM) and, for IFA, onto slides provided in the kit. Tissue cultures (MRC-5 and primary rabbit kidney) were inoculated and examined daily for cytopathogenic effect (CPE). The remaining VTM was frozen at -70 degrees C until tested by the ELISA system. Slides for IFA were stained with HSV common and HSV-2 specific monoclonal antibodies. Of 155 specimens, 47 (30 percent) were unsatisfactory for the IFA test owing to an inadequate number of epithelial cells on the slides. Of 108 adequate specimens, 45 were culture positive; 39 were positive by the IFA test with a sensitivity of 87 percent and a specificity of 90 percent. Of the 39 positives, 29 (75 percent) were correctly classified as type 1 or type 2, six (15 percent) were typed incorrectly, and four (10 percent) were inadequate for typing by the IFA test. All 155 specimens were suitable for testing by the ELISA procedure. Of 55 specimens positive by culture, only 25 (sensitivity 45 percent) were positive by ELISA. However, the specificity was 100 percent. After incubation of two, three, and six days, the tissue cultures detected 71 percent, 89 percent, and 100 percent of the positives, respectively.