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TPS137 Background: The human epidermal growth factor receptors (HER1-4) are frequently overexpressed in human tumors. Increased HER receptor signaling is associated with increased resistance to standard therapies and poor prognosis. TRAS, an anti-HER2 monoclonal antibody, reduces recurrences and improves disease-free survival (DFS) in patients (pts) with HER2+ early BC. However, 15% to 25% of TRAS-treated pts still experience relapsed disease at 5 yrs. NER is a small molecule, irreversible tyrosine kinase inhibitor of HER2 as well as HER1 and HER4. In a phase II study, orally administered NER 240 mg/d was well tolerated with significant antitumor activity in pts with HER2+ BC, with or without prior TRAS (objective response rates of 24% and 56%; median progression-free survival of 22 wks and 40 wks, respectively). The current study will evaluate the efficacy and safety of NER in pts with early-stage HER2+ BC after adjuvant TRAS. Methods: This double-blind, placebo-controlled, multicenter, phase III study w...

TPS152 Background: Bone is a common site of distant recurrence in women with early-stage breast cancer. Cancer cells are thought to stimulate osteoclast-mediated bone resorption, which releases growth factors and cytokines that promote tumor growth. RANK Ligand (RANKL) is the key mediator of osteoclast-induced bone destruction. In preclinical studies, RANKL inhibition reduced the incidence of bone and lung metastases, suppressed tumor progression, and prolonged survival of tumor-bearing mice. Effects were additive with hormonal, chemotherapy, or targeted therapies. Denosumab is a fully human monoclonal antibody against RANKL, approved in the U.S. for the prevention of skeletal-related events in patients with bone metastases from solid tumors. In patients with castrate-resistant prostate cancer, denosumab significantly improved bone metastasis-free survival (BMFS) compared to placebo. The D-CARE trial evaluates BMFS effects of denosumab in women with stage II or III breast cancer. Methods: Women with node-...

BACKGROUND Survivors of out-of-hospital cardiac arrest not associated with acute myocardial infarction are at high risk for recurrent cardiac arrest and sudden cardiac death. The impact of the implantable cardioverter-defibrillator on long-term prognosis in these patients is uncertain. METHODS AND RESULTS Three hundred thirty-one survivors of out-of-hospital cardiac arrest (age, 56 +/- 13.7 years) underwent electrophysiologically guided therapy. Implantable defibrillators were placed in 150 patients (45.3%), and 181 patients (54.7%) received pharmacological and/or surgical therapy alone. Left ventricular ejection fraction was 35.2 +/- 16.6% in defibrillator recipients and 45.3 +/- 18.2% in nondefibrillator patients. Median patient follow-up was 24 months in the defibrillator group and 46 months in the nondefibrillator group. In a proportional hazards model, the independent predictors of total cardiac mortality were left ventricular ejection fraction of less than 0.40 (relative risk, 4.55; 95% confidence interval, 2.44 to 8.33; P = .0001), absence of an implantable defibrillator (relative risk, 2.70; confidence interval, 1.41 to 5.00; P = .017), and persistence of inducible sustained ventricular tachycardia (relative risk, 1.84; 95% confidence interval, 0.97 to 3.49; P = .045). The 1- and 5-year probabilities of survival free of cardiac mortality in patients with left ventricular ejection fraction of less than 0.40 were 94.3% and 69.6% with a defibrillator and 82.1% and 45.3% without a defibrillator, respectively. For patients with left ventricular ejection fraction of 0.40 or more, the 1- and 5-year probabilities of survival free of cardiac mortality were 97.7% and 94.6% with a defibrillator and 95.4% and 86.9% without a defibrillator, respectively. CONCLUSIONS In survivors of out-of-hospital cardiac arrest, the implantable defibrillator is associated with a reduction in cardiac mortality, particularly in patients with impaired left ventricular function.

BACKGROUND & AIMS: Mucin-producing neoplasms (MPNs) of the pancreas include mucinous cystic neoplasms (MCNs) and main-duct, branch-duct, and combined intraductal papillary mucinous neoplasms (IPMNs). MCNs and branch-duct IPMNs are frequently confused; it is unclear whether main-duct, combined, and branch-duct IPMNs are a different spectrum of the same disease. We evaluated their clinical and epidemiologic characteristics. METHODS: Patients who underwent resection for histologically confirmed MPNs were identified (N = 557); specimens were reviewed and eventually reclassified. RESULTS: One hundred sixty-eight patients (30\%) had MCNs, 159 (28.5\%) had branch-duct IPMNs, 149 (27\%) had combined IPMNs, and 81 (14.5\%) had main-duct IPMNs. Patients with MCNs were significantly younger and almost exclusively women; 44\% of patients with main-duct or combined IPMNs and 57\% of those with branch-duct IPMNs were women. MCNs were single lesions located in the distal pancreas (95\%); 11\% were invasive. IPMNs were more frequently found in the proximal pancreas; invasive cancer was found in 11\%, 42\%, and 48\% of branch-duct, combined, and main-duct IPMNs, respectively (P = .001). Patients with invasive MCN and those with combined and main-duct IPMNs were older than those with noninvasive tumors. The 5-year disease-specific survival rate approached 100\% for patients with noninvasive MPNs. The rates for those with invasive cancer were 58\%, 56\%, 51\%, and 64\% for invasive MCNs, branch-duct IPMNs, main-duct IPMNs, and combined IPMNs, respectively. CONCLUSIONS: MPNs comprise 3 different neoplasms: MCNs, branch-duct IPMNs, and main-duct IPMNs, including the combined type. These tumors have specific clinical, epidemiologic, and morphologic features that allow a reasonable degree of accuracy in preoperative diagnosis.

Pneumocystis carinii pneumonia (PCP) continues to be the most common index diagnosis in the acquired immunodeficiency syndrome (AIDS), but it is not clear which of several available agents is the most effective in preventing a recurrence of PCP.We conducted a comparative, open-label trial in 310 adults with AIDS who had recently recovered from an initial episode of PCP and had no treatment-limiting toxic effects of trimethoprim-sulfamethoxazole or pentamidine. All the patients were treated with zidovudine and were randomly assigned to receive either 800 mg of sulfamethoxazole and 160 mg of trimethoprim once daily or 300 mg of aerosolized pentamidine administered every four weeks by jet nebulizer. The participants were followed for a median of 17.4 months.In the trimethoprim-sulfamethoxazole group (n = 154) there were 14 recurrences of PCP, as compared with 36 recurrences (including 1 extrapulmonary recurrence) in the aerosolized-pentamidine group (n = 156). The estimated recurrence rates at 18 months were 11.4 percent with trimethoprim-sulfamethoxazole and 27.6 percent with pentamidine (P0.001). The risk of a recurrence (adjusted for initial CD4 cell count) was 3.25 times higher in the pentamidine group (P0.001, 95 percent confidence interval, 1.72 to 6.16). There were no significant differences between the groups in survival or in hematologic or hepatic toxicity. Crossovers from trimethoprim-sulfamethoxazole to aerosolized pentamidine were more common than the reverse (27 vs. 4 percent), partly because of the study protocols for the management of leukopenia. There were 19 serious bacterial infections in the trimethoprim-sulfamethoxazole group and 38 in the pentamidine group. The time to a first bacterial infection was significantly greater for those assigned to trimethoprim-sulfamethoxazole (P = 0.017).In patients with AIDS who are receiving zidovudine, trimethoprim-sulfamethoxazole is more effective than aerosolized pentamidine in conventional doses for the prevention of recurrent pneumocystis infection.

G A A b st ra ct s reported abdominal complaints as opposed to 7.6% of those without PC(s) (p = 0.589). None of the individuals with PC(s) had pancreatic disease in their medical history. Conclusion: In individuals undergoing preventive medical examination with MRI, the prevalence of PCs was 2.2%. Of these PCs, 5.3% were ≥30 mm, 8% were multilocular and in 10% of cases may represent side-branch IPMN. Cyst presence correlated with increasing age, no difference of prevalence by sex was found. Abdominal complaints did not correlate with PC presence.

This study was designed to assess whether development of the central nervous system (CNS) is delayed in victims of the sudden infant death syndrome (SIDS). We selected the parameter of myelination because it is a continuously changing and readily accessible marker of CNS development in the SIDS age-range. We assessed myelination blindly in 61 SIDS and 89 autopsy controls. In 62 sites the degree of myelination was visually graded in myelin-stained histological sections on an ordinal scale of 0-4 using the inferior cerebellar peduncle as an internal standard of degree 3. Cases were stratified by postconceptional age at death and SIDS and controls were compared with respect to myelin degree at each site. Significantly delayed myelination (p less than 0.05) occurred in the SIDS group in 25 of the 62 sites examined. Hypomyelination affected fiber systems in which myelination is initiated before or after birth and which myelinate with different tempos and preferentially affect pyramidal and cerebellar (somatomotor) and prefrontal-temporal-limbic (visceromotor) systems. Hypomyelination was not associated with individual clinicopathologic variables in the SIDS group. Somatic growth and brain weight were significantly greater in SIDS than controls. Therefore, we suggest that SIDS is associated with a developmental CNS disorder. Although delayed CNS myelination most likely shares a common antecedent with sudden death and is not its cause, the role of somato- and viscero-motor systems in central cardiorespiratory control and arousal warrants further analysis in SIDS.

Statisticians and clinicians involved in the design and conduct of trials of new treatments for the acquired immunodeficiency syndrome (AIDS) have realized that some traditional approaches to the c...

Objective. —To test the ability of a computer-based interview to detect factors related to the risk of the human immunodeficiency virus (HIV) among potential blood donors and to determine donor reactions to the use of the interview. Design. —A comparison of the rate of detection of HIV-related factors elicited by a computer interview with that obtained by standard American Red Cross procedures for assessment of donor suitability, including a randomized crossover trial in which the order of the two methods was reversed. Information obtained by the computer was not available to influence the use of blood components for transfusion. Setting. —The computer interview was administered to donors at an American Red Cross blood donor center and at a mobile blood drive at a hospital. Subjects. —Consecutive sample of 294 male and female blood donors 18 to 75 years of age. Main Outcome Measures. —Subjects' responses to the computer-based interview as well as responses to the standard Red Cross written questionnaires and face-to-face interviews were used for donor assessment. Results. —The interview took an average of 8 minutes to complete. From among 272 donors who provided complete data, the computer identified 12 donors who reported either behaviors associated with a risk of HIV acquisition or symptoms compatible with the acquired immunodeficiency syndrome; none of these donors had been so identified either by routine written questionnaires or by face-to-face interviews used to screen potential blood donors. Only one of the 12 identified donors used the confidential unit exclusion procedure to prevent use of his donated unit. The rate of elicitation of HIV-related factors by the computer interview was 12 (4.4%) of 272 (95% confidence interval [Cl], 2.3% to 7.6%), compared with two (0.13%) of 1536 (95% confidence upper bound, 0.28%) using the standard Red Cross procedure (P Conclusions. —Computer-based screening elicits more HIV-related factors in the health histories of blood donors than do the standard questionnaire and interviewing methods currently in use. Computer-based screening is also acceptable to blood donors. (JAMA. 1992;268:1301-1305)

(2005). A Beginner's Guide to Structural Equation Modeling. Technometrics: Vol. 47, No. 4, pp. 522-522.

4034 Background: Staging systems and nomograms attempt to better stratify patients with pancreatic adenocarcinoma by evaluating different prognostic factors. The purpose of this study is to determi...

Purpose The authors describe the clinicopathologic features of three patients with adult onset foveomacular pigment epithelial dystrophy (AOFPED). Methods The eyes of three patients were studied ophthalmoscopically and by fluorescein angiography, and obtained postmortem and studied by light and electron microscopy. Results Histopathologic study of the three patient's eyes disclosed central loss of the retinal pigment epithelium and photoreceptor cell layer with a moderate number of pigment-containing macrophages present in the subretinal space and outer retina. To either side, the retinal pigment epithelium was distended with much lipofuscin. Basal laminar and basal linear deposits were present throughout the central area. No discontinuities of Bruch membrane were present. Conclusion The findings in the eyes of three patients with AOFPED included marked aging changes that are similar to those seen in age-related macular degeneration. Pigmented cells with lipofuscin in the subretinal space account for the vitelliform appearance.

To determine the impact of clinical presentation variables on the management and survival of patients with gastrointestinal (GI) tract carcinoid tumors.A 20-year (1975-1995) retrospective analysis of 150 patients with GI tract carcinoid tumors at the Massachusetts General Hospital was conducted. Median follow-up was 66 months (range 1-378). Survival estimates for prognostic factors were calculated using Kaplan-Meier product limit estimators, with death from carcinoid as the outcome. Univariate analyses for each factor were obtained using a log-rank test, and multivariate survival analysis was performed.All but two patients underwent surgical intervention with the intent to cure (90%) or debulk the tumor (9%). Mean age at presentation was 55 +/- 18 years (range 11-90). There was a slight female/male predominance (80:70). Symptoms were nonspecific; the most common were abdominal pain (40%), nausea and vomiting (29%), weight loss (19%), and GI blood loss (15%). Incidental carcinoids, discovered at the time of another procedure, occurred in 40% of patients and were noted at multiple sites throughout the GI tract. The distribution of tumors was ileojejunum (37%), appendix (31 %), colon (13%), rectum (12%), stomach (4%), duodenum (1.3%), and Meckel's diverticulum (1.3%). Of the 27 patients with documented liver metastases, carcinoid syndrome developed in only 13 patients (48%), manifested by watery diarrhea (100%), upper body flushing (70%), asthma (38%), and tricuspid regurgitation (23%). All 13 patients with carcinoid syndrome had elevated levels of 5-HIAA, but the absolute levels did not correlate with the severity of symptoms. An additional 11 patients, 3 without liver metastases, had elevated levels of 5-HIAA without any evidence of carcinoid syndrome. Multicentric carcinoid tumors occurred in 15 patients (10%), and all but one of these tumors were centered around the ileocecal valve. There was no difference in the incidence of liver metastases between solitary (18%) and multicentric carcinoids (20%). Synchronous noncarcinoid tumors were present in 33 patients (22%), and metachronous tumors developed in an additional 14 patients (10%) in follow-up. Age and tumor size, depth, and location were significant predictors of metastases. By multivariate analysis, ageor = 50 years, metastases, and male gender were statistically significant predictors of death.Gastrointestinal tract carcinoid tumors have a nonspecific clinical presentation, except in the case of the carcinoid syndrome. Surgical resection is the treatment of choice for improving survival. Surgically treated patients with carcinoid tumor have an overall favorable 83% 5-year survival rate.

SUMMARY This paper proposes a Monte Carlo EM (MCEM) algorithm for fitting the proportional hazards model for interval-censored failure-time data. The algorithm generates orderings of the failures from their probability distribution under the model. We maximize the average of the log-likelihoods from these completed data sets to obtain updated parameter estimates. As with the standard Cox model, this algorithm does not require the estimation of the baseline hazard function. The performance of the algorithm is evaluated using simulations, and the method is applied to data from AIDS and cancer studies. Our results indicate that our method produced more precise and unbiased estimates than methods of right and midpoint imputation.

Background: Evidence that serotonin-active antidepressant medications decrease binge eating in patients with bulimia nervosa has fueled interest in the hypothesis that abnormal serotonergic neurotransmitter function contributes to symptoms of the disorder. To evaluate this hypothesis, we employed pharmacological challenge testing to compare serotonin function in patients with bulimia nervosa and healthy controls. Methods: Neuroendocrine response patterns were compared for 15 nonhospitalized, medication-free, normal-weight women with bulimia nervosa and 14 age-matched healthy female controls. Behavioral assessment included ratings of eating disorder symptoms, depression, and anxiety. Serotonergic response patterns were assessed by measuring the increase in serum prolactin concentration during 5 hours following single- dose, oral administration of 60 mg of d, l-fenfluramine hydrochloride (Pondimin). Results: For patients with bulimia nervosa, the fenfluramine-stimulated increase in serum prolactin concentration was significantly less than for controls. Within the patient group, the frequency of binge eating episodes during the 4 weeks prior to the study exhibited a significant inverse correlation with serotoninstimulated prolactin secretion. Conclusion: Our study provides new evidence that impaired central nervous system serotonergic responsiveness may contribute to the onset or maintenance of abnormal eating patterns in patients with bulimia nervosa.

Objective: To compare the tolerability and efficacy of three oral regimens for the treatment of patients with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia. Desig...

Objective: To examine relations between characteristics of a child's usual source of primary care and involvement of that source before and during hospitalization. Design: Medical record review of pediatric hospitalizations. Setting: All hospitals in Boston, Mass; New Haven, Conn; and Rochester, NY admitting children during the calendar years 1988 through 1990. Patients: The study included 1875 randomly selected pediatric hospitalizations for five diagnostic groups (ie, asthma and other lower respiratory tract disease, abdominal pain [includingappendicitis],meningitis [bacterial and viral], toxic ingestions, and head injury). Hospital records selected were limited to children aged between 1 month and 12 years and residing in the three study communities. Outcome Measures: Whether the primary care source examined the child before admission to the hospital, referred the child to the emergency department, or served as the in-hospital attending physician. Results: Of the medical charts reviewed, 85.7% identified primary care sources. Children in Rochester had higher rates of medical visits before admission ( P P P 2 ) than children in Boston and New Haven. Patterns of primary care involvement also varied by source of care within cities, after controlling for income and severity of illness. Compared with children from Rochester community-based private practices, children in Boston receiving care from health centers, hospitals, or community-based private practices generally had 25% to 50% lower likelihood of positive findings on all primary care involvement measures. Children in New Haven receiving care from community-based private or hospital-based practices also had lower rates, but involvement rates were not higher when they received care from health centers. Other children in Rochester and children receiving care from health maintenance organizations in all cities demonstrated almost no significant differences compared with data from Rochester community practices. Conclusion: The source of primary care is associated with patterns of prehospital and hospital care among hospitalized children, although specific associations vary by city. (Arch Pediatr Adolesc Med. 1996;150:479-486)

An important source of information on the latency period for AIDS is the data from individuals infected by contaminated blood transfusion. However, a difficulty in the analysis and interpretation of these data is that information is available only on individuals who are infected and develop the disease prior to some specific time. In this paper, we propose an approach to the analysis of such data under a proportional hazards model. The proposed approach allows testing for group effects in the presence of multiple explanatory variables.

The proportion of tumor-bearing animals in a chronic bioassay is often used as a basis for assessing risk at human exposure levels that are below the experimental range. However, such a crude experimental tumor rate can be biased by dose-related differences in the nontumor mortality. To adjust tumor rates for competing mortality, Kodell, Gaylor, and Chen (1986, Biometrics 42, 867-873) propose a standardized tumor rate, calculated separately in each dose group from dose-specific estimates of the tumor prevalence and mortality functions. This paper extends the approach of Kodell et al, by developing a method of modeling the standardized rate as a function of dose. An advantage of this approach is that it leads to estimates that are monotone in dose. In addition, by modeling the lifetime risk as a function of dose directly, it is possible to obtain estimates for the risk at dose levels outside the experimental range, such as for low-dose extrapolation, and estimation of the "tumorigenic dose 50" (TD50). A semiparametric model is developed, as well as the nonparametric alternative of isotonic regression. Simulations are provided to show the relative bias and precision of the two approaches to that of Kodell et al.

Between October 1981 and June 1983, the Eastern Cooperative Oncology Group (ECOG) conducted a prospectively randomized trial (EST 1581) of the four most active chemotherapy regimens for metastatic non-small-cell lung cancer (NSCLC). Four hundred eighty-six good performance status patients (PS 0 or 1; 81%) were randomized to receive cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP); mitomycin, vinblastine, and cisplatin (MVP); etoposide and cisplatin (VP-P); or vindesine and cisplatin (VDA-P). All regimens were administered in the doses and schedules originally reported. Complete response (CR) plus partial response (PR) rates for the four regimens were CAMP, 17%; MVP, 31%; VP-P, 20%; and VDA-P, 25%. The response rate for MVP was significantly higher in patients with squamous and adenocarcinoma histologies, but there was no impact on median survival (overall, 24.5 weeks). The duration of response did not differ by treatment as previously suggested for VDA-P. There were 15 CRs (CAMP, one; MVP, six; VP-P, two; VDA-P, six), and 12 patients have survived more than 2 years. Toxicity was significant with 20 treatment-related deaths. CAMP was significantly less toxic than the other regimens (P less than .001). VDA-P demonstrated significantly more life-threatening (seven) and lethal (three) episodes of nephrotoxicity (P less than .001) despite an aggressive hydration program that in itself caused significant morbidity. Analysis of the toxicity data showed, however, that most of the severe toxicity occurred in the 19% of patients who were initially PS 2, suggesting that they are not appropriate candidates for trials of new agents or combinations. None of these regimens can be recommended as a standard therapy for metastatic NSCLC.

This paper develops a nonparametric model of the relationship between survival S and a dichotomous random variable X under the order constraint that P(X=1|S=s) is increasing (or decreasing) with s. The estimation procedure, called isotonic regression, has been studied in some depth for the case of uncensored data, but we give a methodology which is appropriate in the more general context of right, left, and interval censored data. An E-M Algorithm (Dempster et. al., 1977) is used for maximum likelihood estimation.

Although it is evident that working with cancer patients can be stressful, explanations have differed as to why this is so and little attention has been paid to the rewards of this work. One hundred ninety clinical staff members at a comprehensive cancer center representing 91% of eight disciplines studied were interviewed using a semistructured format about the factors influencing their job satisfaction. The fact that the staff members almost uniformly rated their satisfaction as high (8.2 on a scale of 1 to 10) precluded the detection of discriminating variables. Satisfaction with the way they met their goals also was high; most identified potentially achievable goals, relied heavily on the interdisciplinary team, and experienced changes in their attitudes and approach during their first 2 years in the field, primarily increased realism. A major discomfort for physicians was the inability to provide optimal care. Ethical issues were a major discomfort for nurses. Death itself and staff conflict were less important sources of discomfort than in previous reports.

Thallium-201 uptake and clearance after dipyridamole infusion may differ from that after exercise stress because the hemodynamic effects of these two interventions are different. In this study of normal volunteers, thallium kinetics after dipyridamole (n = 13) were determined from three serial image sets (early, intermediate and delayed) and from serial blood samples and compared with thallium kinetics after exercise (n = 15). Absolute myocardial thallium uptake was greater after dipyridamole compared with exercise (p less than 0.0001), although the relative myocardial distribution was similar. The myocardial clearance (%/h) of thallium was slower after dipyridamole than it was after exercise. Comparing dipyridamole and exercise, the differences in clearance were large from the early to the intermediate image (anterior, -11 +/- 17 versus 24 +/- 5, p = 0.0005; 50 degrees left anterior oblique, -7 +/- 11 versus 15 +/- 8, p = 0.004; 70 degrees left anterior oblique, 3 +/- 9 versus 21 +/- 6, p = 0.001). In contrast, the differences in clearance were small from the intermediate to the delayed image (anterior, 15 +/- 4 versus 20 +/- 2, p = 0.025; 50 degrees left anterior oblique, 15 +/- 4 versus 19 +/- 3, p = 0.13; 70 degrees left anterior oblique, 15 +/- 3 versus 18 +/- 2, p = 0.047). Thallium uptake and clearance in the liver, splanchnic region and spleen were greater after dipyridamole (p less than 0.001). Blood thallium levels were greater after dipyridamole (p less than 0.05) and cleared more slowly (p = 0.07). Thus, myocardial thallium-201 uptake and clearance after dipyridamole infusion differ from thallium kinetics after exercise. This difference is, in part, related to associated differences in extracardiac and blood kinetics. Diagnostic criteria for the detection of abnormal thallium-201 clearance must be specific for the type of intervention.

During the last decade, the Eastern Cooperative Oncology Group (ECOG) has studied a series of combination chemotherapy regimens in metastatic (stage IV) non-small-cell lung cancer (NSCLC). In January 1984, the ECOG activated a randomized study, EST 1583, which concluded the evaluation of combination regimens in phase III trials and initiated the evaluation of single agents exclusively in previously untreated patients. The treatment regimens in EST 1583 consisted of: (1) mitomycin, vinblastine, and cisplatin (MVP); (2) vinblastine and cisplatin (VP); (3) MVP alternating with the regimen cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP); (4) carboplatin followed by the MVP regimen at the time of progression; and (5) iproplatin followed by MVP at the time of progression. From January 1984 to July 1985, 743 patients were entered on this trial and 699 fulfilled the eligibility requirements. The following objective response rates (complete plus partial remissions) were observed: first-line MVP, 20%; VP, 13%; MVP/CAMP, 13%; carboplatin, 9%; iproplatin, 6%; and second-line MVP, 6%. First-line MVP produced a significantly higher response rate than the other treatments (P = .03) adjusted for prognostic variables. Using analyses that were adjusted for prognostic covariates, survival for patients treated on a given regimen was compared with survival for all remaining patients. These analyses showed that treatment with carboplatin was associated with longer survival (median survival time, 31.7 weeks; P = .008) while initial treatment with MVP was associated with a trend for shorter survival (median survival time, 22.7 weeks; P = .09). It should be noted that none of these regimens appear to have produced a clinically meaningful prolongation of survival. Similar analyses evaluating time to progression disclosed that carboplatin-treated patients had a significantly longer time to progression (median time to progression, 29 weeks) than all remaining patients (P = .01). Life-threatening and lethal toxicities (toxicity grades 4 and 5) were greater on the combination regimens than on the single agents (P less than .0001). Based on these results, current group-wide ECOG trials in stage IV NSCLC consist of randomized phase II trials evaluating single agents.

We examined the role of electrophysiologic testing in the prediction of long-term outcome in 166 survivors of out-of-hospital cardiac arrest not associated with acute myocardial infarction. Ventricular arrhythmias were inducible in 131 patients (79 percent) at base line and were suppressed by antiarrhythmic drugs or surgery (or both) in 91 of 127 (72 percent). During a median follow-up period of 21 months, cardiac arrest recurred in 29 patients: 11 (12 percent) of the 91 in whom inducible arrhythmias had been suppressed (including 5 patients in whom treatment had been discontinued), 12 (33 percent) of the 36 in whom inducible arrhythmias persisted, and 6 (17 percent) of the 35 in whom arrhythmias could not be induced at the initial electrophysiologic study. Cox survival analysis identified the following three variables as significant independent predictors of recurrent cardiac arrest: persistence of inducible ventricular arrhythmias (relative risk, 3.97 [95 percent confidence interval, 1.80 to 8.75], P = 0.0006), a left ventricular ejection fraction of 30 percent or less (relative risk, 2.60 [1.21 to 5.53], P = 0.0138), and the absence of cardiac surgery (relative risk, 4.20 [0.99 to 17.77], P = 0.0512). We conclude that electrophysiologic testing is useful in quantifying the subsequent risk of cardiac arrest among survivors of out-of-hospital cardiac arrest.

Data from 100 patients with life-threatening ventricular arrhythmias and automatic implantable cardioverter defibrillators (AICDs) were analyzed to determine if clinical, angiographic and electrophysiologic variables are predictive of AICD discharge. During a median follow-up period of 18 months, 45% of patients experienced greater than or equal to 1 device discharge during a documented ventricular arrhythmia or in association with presyncope or syncope ("appropriate" AICD discharge). Univariate predictors of appropriate AICD discharge included depressed left ventricular ejection fraction (p = 0.0007), inducible sustained ventricular arrhythmia at electrophysiologic study performed in the absence of antiarrhythmic drugs (p = 0.009), fewer number of extrastimuli required for induction at this study (p = 0.001), inducible sustained arrhythmia at electrophysiologic study performed on the discharge antiarrhythmic regimen (p = 0.0005) and fewer extrastimuli required for this induction (p less than 0.0001). Multivariate analysis identified the induction of a sustained ventricular arrhythmia by 1 or 2 extrastimuli during electrophysiologic study performed on the discharge regimen as the only independent predictor among the variables analyzed (p less than 0.0001). The probability of appropriate AICD discharge at 18 months was 86% for patients who had a sustained arrhythmia induced with 1 or 2 extrastimuli versus 15% for those requiring 3 extrastimuli for arrhythmia induction and 13% for patients without inducible sustained arrhythmias.

Short-term efficacy of transcatheter intracardiac electric shock was evaluated in 25 patients with recurrent sustained ventricular tachycardia (VT) secondary to coronary artery disease. Pace mapping and activation sequence mapping during VT were both used to direct intracardiac electric shocks applied between the distal electrode of the catheter (cathode) and a chest wall plate (anode) using a mean total energy of 588 ± 209 J/patient. The short-term outcome of the procedure was considered successful in 3 patients (12%) who neither developed spontaneous VT nor had sustained VT in response to programmed electrical stimulation 1 week after the procedure. The short-term outcome in the remaining 22 patients (88%) was considered unsuccessful: 7 of the 22 patients developed spontaneous sustained VT and in 19 patients, including 15 with no spontaneous VT, sustained VT was still inducible by programmed electrical stimulation 7 ± 2 days after the intracardiac electric shock. All 22 patients were subsequently treated with other modes of antiarrhythmic therapy. Using the technique described, the short-term efficacy of map-directed transcatheter intracardiac electric shock in eliminating VT is poor.

The electrophysiologic effects and antiarrhythmic efficacy of oral sotalol were investigated in 42 patients with coronary artery disease and prior myocardial infarction who presented with ventricular tachycardia (VT), ventricular fibrillation (VF) or syncope. The mean left ventricular ejection fraction was 36 +/- 9%. Baseline programmed cardiac stimulation initiated sustained VT (26 patients) or VF (16). The induced arrhythmia was not suppressed by conventional antiarrhythmic drugs in any patient (3 +/- 2 trials/patient). The mean daily dosage of sotalol was 221 +/- 84 mg. The right ventricular effective refractory period increased from 247 +/- 25 to 273 +/- 26 ms with sotalol (p = 0.0001) and the corrected QT interval increased from 431 +/- 35 to 456 +/- 62 ms (p = 0.02). Arrhythmia suppression was defined as no sustained VT or VF in response to programmed cardiac stimulation using up to 3 extrastimuli. Induced VT or VF was suppressed by sotalol therapy in 10 (24%) patients (group 1). Group 1 patients had faster induced arrhythmias at the baseline study than patients whose induced ventricular arrhythmia was not suppressed (group 2). The mean left ventricular ejection fraction tended to be higher in group 1 patients (p = 0.07). Fourteen patients (including 9 group 1 patients) continued receiving sotalol after discharge. In 2 group 2 patients, sotalol was combined with a class IA antiarrhythmic drug. During a mean follow-up period of 7.9 +/- 4.9 months, 2 patients had recurrent VT and in 2 others sotalol was discontinued due to side effects.

Between December 1979 and June 1983 the Eastern Cooperative Oncology Group (ECOG) treated 893 good-performance status patients with metastatic non-small-cell lung cancer (NSCLC) on one of seven phase III combination chemotherapies. The overall median survival was 23.5 weeks with no significant differences between treatments. One hundred sixty-eight patients (19%) survived greater than 1 year and 36 (4%) for greater than 2 years. The etoposide-platinum combination had the highest proportion of 1-year survivors (25%). Mitomycin-vinblastine-platinum (MVP), which had demonstrated the highest response rate, had significantly fewer 1-year survivors (12%) than any other regimen (P = .003). Analysis of pretreatment characteristics that distinguished patients who survived greater than 1 year from those who did not demonstrated that an initial performance status of 0, no bone metastases, female sex, no subcutaneous metastases, non-large-cell histology, less than 5% prior weight loss, no symptoms of shoulder or arm pain, and no liver metastases were predictors of longer survival. Of particular interest was the finding that response duration was significantly longer (P = .002) for those patients who experienced a longer time to best response. In addition, patients who survived greater than 1 year experienced greater degrees of nonlethal toxicity, in particular, gastrointestinal and hematologic, than patients who did not survive 1 year, (P = .006). A detailed chart review of 32 2-year survivors and 32 matched controls demonstrated that maintenance or improvement of performance status and maintenance of serum albumin levels at 3 months from the initiation of treatment were both important predictors of longer survival.

Nuclear magnetic resonance (NMR) imaging has shown potential in the detection and characterisation of acute myocardial infarction in humans. This study was performed to evaluate the capability of NMR imaging in the measurement of infarct size in patients with recent myocardial infarction. Electrocardiograpic (ECG)-gated spinecho NMR imaging was performed in 26 patients a mean of 9 ± 3 days (range 5 to 20) after infarction. The imaging technique used provided single-slice, spin-echo (time to echo [TE] = 60 ms) images of the left ventricle in its true short axis, allowing direct correlation of NMR infarct location and size with the region of severe hypokinesia on left ventriculography. In all 20 patients with complete NMR studies, infarct location was correctly identified by using specific, objective criteria. The correlation between the mean infarct volume (29 ± 11 ml) and the quantitated left ventricular hypokinetic segment (7.1 ± 4.0 cm) was good (r = 0.84, p = 0.0002), suggesting that NMR imaging of the heart may have a role in the noninvasive assessment of myocardial infarct size in patients.

The purpose of this study was to determine the prognostic utility of quantitative exercise thallium-201 imaging and compare it with that of cardiac catheterization in ambulatory patients. Accordingly, long-term (4 to 9 years) follow-up was obtained in 293 patients who underwent both tests for the evaluation of chest pain: 89 had undergone coronary artery bypass graft surgery within 3 months of testing and were excluded from analysis, 119 experienced no cardiac events and 91 had an event (death in 20, nonfatal myocardial infarction in 21 and coronary artery bypass operations performed greater than 3 months after cardiac catheterization in 50). When all variables were analyzed using Cox regression analysis, the quantitatively assessed lung/heart ratio of thallium-201 activity was the most important predictor of a future cardiac event (chi 2 = 40.21). Other significant predictors were the number of diseased vessels (chi 2 = 17.11), patient gender (chi 2 = 9.43) and change in heart rate from rest to exercise (chi 2 = 4.19). Whereas the number of diseased vessels was an important independent predictor of cardiac events, it did not add significantly to the overall ability of the exercise thallium-201 test to predict events. Furthermore, information obtained from thallium-201 imaging alone was marginally superior to that obtained from cardiac catheterization alone (p = 0.04) and significantly superior to that obtained from exercise testing alone (p = 0.02) in determining the occurrence of events. In addition, unlike the exercise thallium-201 test, which could predict the occurrence of all categories of events, catheterization data were not able to predict the occurrence of nonfatal myocardial infarction. The exclusion of bypass surgery and previous myocardial infarction did not alter the results. In conclusion, data from this study demonstrate that exercise thallium-201 imaging may be superior to data from both exercise testing alone and cardiac catheterization data alone for predicting future events in ambulatory patients who have undergone both exercise thallium-201 imaging and catheterization for the evaluation of chest pain.

Thrombolytic therapy is associated with a bleeding tendency that may be exacerbated by adjunctive antiplatelet agents. The effect of recombinant tissue-type plasminogen activator (rt-PA) alone or in combination with aspirin on serial measurements of template bleeding time, ex vivo platelet aggregation and coagulation factors and the frequency of bleeding was studied in dogs. During infusion of rt-PA (15, 30 or 60 micrograms/kg per min for 90 min), a dose-related increase in bleeding time was observed. In a randomized blinded study of 25 dogs, the baseline bleeding time (mean +/- SD) was 3.5 +/- 1 min in control animals and 4 +/- 2 min after oral aspirin (15 mg/kg body weight). Infusion of rt-PA (15 micrograms/kg per min for 90 min) prolonged the bleeding time to a maximum of 15 +/- 12 min. In contrast, combined aspirin and rt-PA therapy produced an increase to greater than 30 min during infusion, reverting to 13 +/- 10 min within 2 h after cessation of infusion. Recurrent continuous bleeding from incision sites occurred in one of six dogs given aspirin alone, two of seven given rt-PA alone and all six dogs given both aspirin and rt-PA (p = 0.02). Bleeding time greater than 9 min correlated significantly with bleeding frequency (p less than 0.0001), with a sensitivity of 100% and a specificity of 87%. Intravenous bolus injection of aprotinin (20,000 kallikrein inhibitor units/kg body weight) in six dogs given both rt-PA and aspirin produced a decrease in bleeding time from greater than 30 min to 9.5 +/- 9 min and resulted in cessation of bleeding. Thus, bleeding and bleeding time prolongation in this canine model are potentiated by a marked interactive effect of rt-PA and aspirin that is rapidly reversible. Template bleeding times may provide a useful quantitative index for monitoring the bleeding tendency associated with thrombolytic therapy.

We studied the value of thallium imaging as compared with clinical and exercise-test variables in predicting cardiac events occurring over five years in 525 consecutive patients referred for thallium-exercise testing in 1979. Follow-up was obtained on 467 patients (89 percent). There were 105 cardiac events--25 cardiac deaths, 33 myocardial infarctions, and 47 coronary bypass procedures. A Cox survival analysis identified increased thallium uptake by the lungs, a marker of left ventricular dysfunction during exercise, as the best predictor of a cardiac event (relative risk ratio = 3.5; 95 percent confidence interval, 2.2 to 5.4). The next most powerful predictors were a history of typical angina, a previous myocardial infarction, and ST-segment depression during exercise (relative risk ratios = 2.1, 1.8, and 1.7, respectively). No combination of variables made up for the loss in prognostic power when the variable of increased thallium uptake by the lungs was removed from the model. Cardiac events occurred over five years in 10 (5 percent) of 192 patients with a normal thallium scan, 41 (25 percent) of 163 patients with an abnormal thallium scan but normal thallium activity in the lungs, and 54 (67 percent) of 81 patients with increased thallium uptake by the lungs (P less than 0.0001). We conclude that increased uptake of thallium by the lungs during exercise predicts a high risk of subsequent cardiac events.

Increases in plasma creating kinase-MB (MB CK) were correlated with the onset of coronary artery reperfusion determined angiographically in 32 patients with acute myocardial infarction who were treated with, recombinan' human tissue-type plasminogen activator (rt-PA). Reperfusion occurred in 14 (70%) of 20 patients with left anterior descending coronary artery occlusion and in 8 (73%) of 11 patients with right coronary artery occlusion. One patient had persistent left circumflex coronary artery occlusion. Plasma MB CK levels (radioimmunometric assay) did not increase significantly in patients with persistent occlusion, but increased by a mean (± SEM) of 8 ± 1 and 6 ± 1 times over pretreatment levels at the end of the infusion in patients with a reperfused left anterior descending and right coronary artery, respectively. When a ≥2.5-fold increase in MB CK levels at the end of the rt-PA infusion was taken as evidence of reperfusion of the left anterior descending coronary artery, 13 (93%) or 14 patients with reperfusion and 5 (83%) of 6 with persistent occlusion were correctly identified. When a ≥2.2-fold increase in MB CK levels was used to identify right coronary artery reperfusion, seven (89%) of eight patients with reperfusion and three (100%) of three patients with persistent occlusion were correctly identified. The sensitivity and specificity of these indexes, derived from and applied to the same patient group, were 91 and 89%, respectively.These indexes were then applied prospectively to 16 patients wth anterior, 16 with inferior and 5 vilh inferoposterier infarction in whom MB CK was assayed hoth before and at completion of a 90 min rt-PA infusion and coronary angiography performed at 90 min. Of 13 patients with anterior infarction and a patent left anterior descending coronary artery, 12 (92%) demonstrated a ≥2.5-fold increase in MB CK, whereas all 3 patients with a persistently occluded artery had a smaller increase. Of 13 patients with inferior infarction and a patent right coronary artery, 10 (77%) had a ≥2.2-fold increase in MB CK, whereas the 3 patients with persistent occlusion had a